Systematic review
Meta-analysis of ultrasound-guided biopsy of suspicious axillary lymph nodes in the selection of patients with extensive axillary tumour burden in breast cancer B. J. van Wely1 , J. H. W. de Wilt2 , C. Francissen4 , S. Teerenstra3 and L. J. A. Strobbe1 1 Department
of Surgery, Canisius Wilhelmina Hospital, and 2 Department of Surgery and 3 Section of Biostatistics, Department of Health Evidence, Radboud University Medical Centre, Nijmegen, and 4 Department of Surgery, Geldersche Vallei Hospital, Ede, The Netherlands Correspondence to: Dr B. J. van Wely, B62, Department of Surgery, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands (e-mail: [email protected])
Background: Recent studies show that not all patients with breast cancer and positive axillary lymph
nodes need additional axillary surgery. A systematic review and meta-analysis of the literature was performed to test the hypothesis that ultrasound-guided biopsy of suspicious nodes can be a useful tool to identify patients with extensive axillary tumour burden. Methods: PubMed and Embase were searched to identify articles reporting on ultrasound-guided techniques to stage the axilla of patients with breast cancer. The emphasis was to study the number of positive nodes found after axillary lymph node dissection (ALND) following a positive ultrasound-guided biopsy or a positive sentinel lymph node biopsy (SLNB). Information regarding the number of positive nodes thus had to be available. Results were tested for heterogeneity and a meta-analysis was performed. Results: A total of 894 articles were identified, and 115 were selected based on title and abstract information by two independent reviewers. After extensive review, 18 articles were eligible for analysis. Eight studies reported sufficient data to perform a meta-analysis comparing 532 patients with a positive ultrasound-guided biopsy with 248 patients with a negative ultrasound-guided biopsy but a positive SLNB. The number of involved nodes was significantly higher in patients in whom axillary metastasis was detected by ultrasound-guided biopsy (P < 0⋅001). No heterogeneity in the observed effect was found (I 2 = 22 per cent, P = 0⋅26). Conclusion: Patients with breast cancer in whom axillary metastases are detected by ultrasound-guided biopsy have significantly more involved nodes than SLNB-positive patients. This finding enables further preoperative tailoring of axillary treatment in breast cancer. Presented to the 32nd Congress of the European Society of Surgical Oncology, Valencia, Spain, September 2012 Paper accepted 1 September 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9663
Introduction
In breast cancer, axillary lymph node involvement is an important prognostic factor. Patients without axillary involvement have a significantly better prognosis than patients with N1–3 disease1,2 . Before the introduction of sentinel lymph node biopsy (SLNB), elective axillary lymph node dissection (ALND) was performed in all patients. After the introduction and validation of SLNB to stage the axilla, ALND was omitted in patients with a negative SLNB3,4 . In patients with a positive SLNB, additional ALND is usually performed, and the number of positive nodes found by the pathologist as well as the © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
total number of nodes retrieved during ALND (positive and negative) have clinical importance. The correlation between the number of positive nodes found and the number of nodes retrieved is known as the lymph node ratio (LNR). Several publications have established that the LNR is also a strong prognostic factor – even more predictive of outcome than N category5 – 7 . However, with the effective systemic adjuvant treatment currently available, the need for ALND in all node-positive patients is under debate. The Z0011 trial8,9 reported good locoregional control and overall survival rates in patients with limited tumour burden (fewer than 3 positive nodes) who did not undergo ALND. Although this study was BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
underpowered, the results have been confirmed by several other studies10,11 . Thus, the preoperative diagnostic pathway for patients with newly diagnosed breast cancer should ideally have a diagnostic tool to differentiate between patients with limited (3 or fewer positive nodes, or N1) and more extensive (more than 3 positive nodes, or N2) axillary tumour burden. Routine axillary ultrasonography in case of a malignant breast lesion is advocated by the UK National Institute of Care and Health Excellence (NICE)12 and Dutch13 breast cancer guidelines. In the case of ultrasonographically suspicious lymph nodes (defined as nodes that are rounder, have an asymmetrical cortex, are thicker than 3 mm or have lost the hyperechoic hilum14 ), ultrasound-guided core needle biopsy (CNB) or fine-needle aspiration cytology (FNAC) should be used to detect axillary metastasis before surgery. When pathological analysis confirms metastasis in the lymph node, these patients do not have to undergo SLNB and can proceed directly to ALND. The sensitivity and specificity of ultrasound-guided techniques to stage the axilla have been reported by many authors. A recent meta-analysis15 on the subject revealed median sensitivity of 79⋅6 per cent and median specificity of 98⋅3 per cent. A recent analysis16 of the prospective database in the breast cancer unit at Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, showed significantly more involved nodes in patients with positive ultrasound-guided FNAC than in patients in whom axillary involvement was diagnosed by SLNB (for both ultrasonographically suspicious and non-suspicious nodes). This finding led to the hypothesis that ultrasound-guided biopsy techniques might be a useful diagnostic tool to differentiate between more or less extensive axillary tumour burden in patients with breast cancer. To test this hypothesis, a systematic review of the literature was performed and a meta-analysis conducted.
Review inclusion and exclusion criteria Articles had to be published in English. The aim of the review was to identify original articles that reported on a cohort of patients with breast cancer in whom ultrasound-guided biopsy techniques were used to stage the axilla. In studies that report on the number of positive nodes after ultrasound-guided biopsy, three distinctive groups of node-positive patients can be identified: patients who have ALND after a positive ultrasound-guided biopsy of suspicious nodes (US+/biopsy+); patients with a negative ultrasound-guided biopsy of ultrasonographically suspicious nodes but a positive SLNB (US+/biopsy−/SLNB+); and patients with no ultrasonographically suspicious nodes who have a positive SLNB (US−/SLNB+) (Fig. 1). To be eligible for review, articles should have reported on the number of positive nodes found at ALND after positive ultrasound-guided biopsy and positive SLNB findings. Information for at least two of the subgroups mentioned above had to be available. When not all information on positive nodes was available, effort was made to calculate this from the data provided. Where the data were insufficient, the corresponding author was contacted. Failure to meet the above criteria resulted in exclusion from the review. Because the main interest was to evaluate ultrasound-guided techniques used to stage the axilla of all patients with breast cancer, articles that reported only
All patients with breast cancer Ultrasound imaging of axilla
Suspicious nodes
No suspicious nodes
Ultrasound-guided biopsy
Methods
Literature search A literature search was performed in PubMed and Embase. Search terms used were ‘Ultrasound’, ‘Breast Cancer’ and ‘Axillary’; literature search details are shown in Table S1 (supporting information). To complete the search, related articles were searched, as well as references within selected articles. Two reviewers independently selected potentially relevant papers based on title and abstract. Discrepancies between the reviewers were resolved by consensus. The literature search was last updated in September 2013. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Positive
Negative
SLNB
Positive
Negative
SLNB
Positive
Negative
Axillary lymph node dissection
Flow chart showing how patients could be allocated to axillary lymph node dissection in the included studies. SLNB, sentinel lymph node biopsy
Fig. 1
www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
Records identified through PubMed search n = 852
Records identified through Embase search n = 884
Records after duplicates removed n = 894 Records excluded (did not meet inclusion criteria) n = 779 Title and abstract selection n = 115 Articles excluded (did not meet exclusion criteria) n = 51 Full-text articles assessed for eligibility n = 64 Full-text articles excluded n = 46 No. of nodes after ALND not stated n = 40 No response from author n = 6 Articles accepted for review n = 18 Fig. 2
PRISMA flow diagram for the study. ALND, axillary lymph node dissection
Table 1
Articles included in the review Baseline study results
Reference
Year
QUADAS score (0–14)
Bonnema et al.18 Damera et al.19 Kuenen-Boumeester et al.20 Lemos et al.21 de Kanter et al.22 van Rijk et al.23 Davis et al.24 Ciatto et al.25 Nori et al.26 Hinson et al.27 Holwitt et al.28 Tahir et al.29 Swinson et al.30 Rao et al.31 Schiettecatte et al.32 García Fernández et al.33 Solon et al.34 van Wely et al.16
1997 2003 2003 2005 2006 2006 2006 2007 2007 2008 2008 2008 2009 2009 2010 2011 2012 2013
11 12 12 8 9 12 10 10 9 9 10 8 11 9 10 12 11 12
Total
No. of patients
No. of US+ patients
150 103 183 40 161 732 37 476 132 112 256 38 369 47 148 520 445 1448
93 (62⋅0) 54 (52⋅4) 183 (100) 10 (25) n.s. 176 (24⋅0) 22 (59) 476 (100) 31 (23⋅5) 61 (54⋅5) 110 (43⋅0) 38 (100) 114 (30⋅9) 47 (100) 58 (39⋅2) 96 (18⋅5) 121 (27⋅2) 234 (16⋅2)§
5397
Node-positive patients and detection method used
No. of ultrasound-guided biopsies 81 54 183 10 161 176 22 488 14† 61 110 38 111 47 55 96 121 234 2062
No. of node-positive patients 62 (41⋅3) 46 (44⋅7) 85 (46⋅4) 11 (28) 79 (49⋅1) 271 (37⋅0) n.s. 308 (64⋅7) 42 (31⋅8) 58 (51⋅8) 113 (44⋅1) 17 (45) 116 (31⋅4) 38 (81) 65 (43⋅9) 177 (34⋅0) 210 (47⋅2) 572 (39⋅5)§
US+/ US+/biopsy−/ biopsy+ * SLNB+
US−/ SLNB+
39 27 40 (3) 6 31 59 (1) 15 206 (7) 11 34 74 8 39 30 34 76 110 157
10 8 48 2 48 36 3 109 1 10 9 9 12 8 7 8 0 19
13 11 n.s. 3 n.s. 177 4 n.s. 23‡ 14 30 n.s. 65 n.s. 24 93 100 376
996
347
933
Values in parentheses are percentages unless indicated otherwise; *values in parentheses are number of false-positive biopsies. †Seventeen patients with suspicious nodes on initial ultrasound imaging (US+) did not undergo ultrasound-guided biopsy; ‡data were missing for seven node-positive patients; §35 patients were excluded because of indifferent findings on fine-needle aspiration cytology, 20 of whom were node-positive. biopsy+, Positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; n.s., not stated.
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
Table 2 Summary of studies included in meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with a negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy US+/biopsy+
US+/biopsy−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Ciatto et Damera et al.19 de Kanter et al.22 Hinson et al.27 Kuenen-Boumeester et al.20 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
206 27 31 34 37 6 34 157
89 (43.2) 9 (33) 15 (48) 15 (44) 17 (46) 5 (83) 15 (44) 69 (43⋅9)
117 (56⋅8) 18 (67) 16 (52) 19 (56) 20 (54) 1 (17) 19 (56) 88 (56⋅1)
109 8 48 10 45 2 7 19
71 (65⋅1) 7 (88) 38 (79) 10 (100) 41 (91) 2 (100) 7 (100) 13 (68)
38 (34⋅9) 1 (12) 10 (21) 0 (0) 4 (9) 0 (0) 0 (0) 6 (32)
Total
532
234 (44⋅0)
298 (56⋅0)
248
189 (76⋅2)
59 (23⋅8)
Reference al.25
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy. No. of patients with 1–3 nodes Reference al.25
Ciatto et Damera et al.19 de Kanter et al.22 Hinson et al.27 Kuenen-Boumeester et al.20 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16 Total
US+/biopsy+ US+/biopsy–/SLNB+ Weight (%)
Risk ratio
89 of 206 9 of 27 15 of 31 15 of 34 17 of 37 5 of 6 15 of 34 69 of 157
71 of 109 7 of 8 38 of 48 10 of 10 41 of 45 2 of 2 7 of 7 13 of 19
27·6 5·8 11·8 11·7 13·4 5·1 10·8 13·9
0·66 (0·54, 0·82) 0·38 (0·21, 0·69) 0·61 (0·41, 0·90) 0·46 (0·31, 0·69) 0·50 (0·35, 0·72) 0·94 (0·50, 1·78) 0·47 (0·31, 0·71) 0·64 (0·45, 0·91)
234 of 532
189 of 248
100·0
0·57 (0·49, 0·67)
Heterogeneity: τ2 = 0·01; χ2 = 8·95, 7 d.f., P = 0·26; I2 = 22% Test for overall effect: Z = 7·22, P < 0·001
Risk ratio
0·01
0·1 More nodes in US+/biopsy+
1
10
100
More nodes in US+/biopsy–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with a negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy
Fig. 3
on patients with a high risk of axillary metastasis were excluded.
Study quality assessment The QUADAS tool, a validated quality assessment tool for diagnostic accuracy studies, was used to assess the quality of included articles17 . The checklist contains 14 items that can be scored for each study; each characteristic mentioned or available in the article scores one point; the maximum score is thus 14.
not be calculated. In addition, it was not possible to distinguish between one or two and more than two involved nodes, as defined in the Z0011 trial8,9 . The number of patients with N1 or N2 disease was compared between the different subgroups (US+/biopsy+ versus US+/biopsy−/ SLNB+, US+/biopsy+ versus US−/SLNB+, and US+/ biopsy−/SLNB+ versus US−/SLNB+). In the metaanalysis, the proportions of node-positive patients with one to three positive nodes in the various groups were compared. However, in the interpretation of the results, the number of patients with more than three involved nodes is of particular interest.
Number of positive nodes involved Because no source data on the total number of nodes were available, only the number of patients with one to three (N1 disease) or more than three (N2 disease) positive nodes could be documented. For this reason, the LNR could © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Statistical analysis To compare the number of positive nodes between the three groups, a random-effects meta-analysis with Cochrane–Mantel–Haenszel weighting was performed www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
Summary of studies included in meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy
Table 3
US+/biopsy+
US−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Damera et Hinson et al.27 Holwitt et al.28 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
27 34 74 6 34 157
9 (33) 15 (44) 65 (88) 5 (83) 15 (44) 69 (43⋅9)
18 (67) 19 (46) 9 (12) 1 (17) 19 (46) 88 (56⋅1)
11 14 30 3 24 376
11 (100) 14 (100) 12 (40) 2 (67) 24 (100) 256 (68⋅1)
0 (0) 0 (0) 18 (60) 1 (33) 0 (0) 120 (31⋅9)
Total
332
178 (53⋅6)
154 (46⋅4)
458
319 (69⋅7)
139 (30⋅3)
Reference al.19
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; US−, no suspicious nodes on initial ultrasound imaging; SLNB+, positive nodes on sentinel lymph node biopsy.
No. of patients with 1–3 nodes Reference
US+/biopsy+
US–/SLNB+
Weight (%)
Risk ratio
9 of 27 15 of 34 65 of 74 5 of 6 15 of 34 69 of 157
11 of 11 14 of 14 12 of 30 2 of 3 24 of 24 256 of 376
16·1 17·7 17·0 12·0 17·8 19·4
0·35 (0·21, 0·60) 0·46 (0·31. 0·67) 2·20 (1·41, 3·43) 1·25 (0·52, 3·00) 0·45 (0·31, 0·66) 0·65 (0·53, 0·78)
178 of 332
319 of 458
100·0
0·69 (0·43, 1·12)
Damera et al.19 Hinson et al.27 Holwitt et al.28 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16 Total
Heterogeneity: τ2 = 0·30; χ2 = 44·09, 5 d.f., P < 0·001; I2 = 89% Test for overall effect: Z = 1·51, P = 0·13
Risk ratio
0·01
0·1
More nodes in US+/biopsy+
1
10
100
More nodes in US–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; US−, no suspicious nodes on initial ultrasound imaging; SLNB+, positive nodes on sentinel lymph node biopsy
Fig. 4
of the percentage of patients with one to three positive nodes, using Review Manager (RevMan) version 5.0 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). As a summary measure, the ratio of these percentages was used. Studies were included in the meta-analysis if this percentage was present in, or could be estimated from, the reported results. In addition, the results of the meta-analysis were compared qualitatively with findings from other studies (not included in the meta-analysis because of missing data), provided these studies reported on both groups. Heterogeneity was tested for, and a funnel plot was used to test for publication bias. P < 0⋅050 was considered statistically significant.
eligible articles. References from the two searches were combined, resulting in 894 articles that were available for title and abstract reviewing. This process led to the exclusion of 779 articles that did not meet inclusion criteria. Following extensive review of 115 eligible articles, a further 51 articles were excluded because inclusion criteria were not met. Sixty-four articles reported on ultrasound-guided techniques to stage the axilla, but 46 of these did not report all data necessary for inclusion, or reported on a specific subset of patients, thereby introducing a selection bias. These 46 articles were excluded from further review. A total of 18 articles met the inclusion criteria and were eligible for review and meta-analysis (Fig. 2). Detailed information on the reviewed articles16,18 – 34 is displayed in Table 1.
Results
Literature search
Data analysis
A total of 852 articles were found in the PubMed database search, and the Embase search resulted in 884 potentially
Of the 18 articles selected for review, ten provided sufficient data on the number of patients with N1 and N2
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
Table 4 Summary of studies included in meta-analysis comparing patients with negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy US+/biopsy−/SLNB+
US−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Damera et Davis et al.24 Hinson et al.27 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
8 3 10 2 7 19
7 (88) 3 (100) 10 (100) 2 (100) 7 (100) 13 (68)
1 (12) 0 (0) 0 (0) 0 (0) 0 (0) 6 (32)
11 4 14 3 24 376
11 (100) 4 (100) 14 (100) 2 (67) 24 (100) 256 (68⋅1)
0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 120 (31⋅9)
Total
49
42 (86)
7 (14)
432
311 (72⋅0)
121 (28⋅0)
Reference al.19
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; US−, no suspicious nodes on initial ultrasound imaging.
No. of patients with 1–3 nodes Reference Damera et al.19 Davis et al.24 Hinson et al.27 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
US+/biopsy–/SLNB+ US–/SLNB+ 7 of 8 3 of 3 10 of 10 2 of 2 7 of 7 13 of 19
11 of 11 4 of 4 14 of 14 2 of 3 24 of 24 256 of 376
42 of 49 311 of 432 Total Heterogeneity: τ2 = 0·00; χ2 = 1·10, 5 d.f., P = 0·95; I2 = 0% Test for overall effect: Z = 0·20, P = 0·84
Weight (%)
Risk ratio
10·8 4·8 41·9 1·3 30·4 10·9
0·87 (0·63, 1·19) 1·00 (0·62, 1·60) 1·00 (0·85, 1·17) 1·33 (0·54, 3·32) 1·00 (0·83, 1·21) 1·00 (0·73, 1·37)
100·0
0·99 (0·89, 1·10)
Risk ratio
0·5
0·7
1
More nodes in US+/biopsy–/SLNB+
1·5
2
More nodes in US–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; US−, no suspicious nodes on initial ultrasound imaging
Fig. 5
disease in at least two groups. The other eight articles provided information on the number of involved nodes, but could not be included in the meta-analysis because only the median number of positive nodes was provided. Only a limited number of articles reported on the number of patients in whom only micrometastasis was detected. There were two studies in the US+/biopsy−/ SLNB+ group; the number of node-positive patients with only micrometastases was three of three24 and five of seven32 . In the US−/SLNB+ group, three studies reported on micrometastasis: 14 of 24 patients32 , 20 of 2326 and 20 per cent (absolute numbers not given)33 had only micrometastasis. The results of the meta-analysis were compared qualitatively to findings in these studies, provided that the studies reported on both groups.
US+/biopsy+ versus US+/biopsy−/SLNB+ Eight studies16,19 – 22,25,27,32 provided data on the percentage of patients with one to three positive nodes found at ALND, enabling 532 patients with a positive ultrasound-guided biopsy (US+/biopsy+) to be compared with 248 patients with a negative ultrasound-guided biopsy but a positive SLNB (US+/biopsy−/SLNB+). The number of patients with one to three positive nodes was 234 (44⋅0 per cent) and 189 (76⋅2 per cent) respectively. Absolute numbers and the results of the meta-analysis are shown in Table 2 and Fig. 3. The forest plot shows consistency of the observed effect: all risk ratios were less than 1⋅00, and all but one study21 also had confidence intervals below 1⋅00. This indicates that significantly more patients in the US+/biopsy+ group had more than three involved nodes. No indication of heterogeneity was found between the studies
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
(I 2 = 22 per cent, P = 0⋅26), and the funnel plot showed no indication of publication bias. The meta-analysis thus provides strong evidence that the number of nodes is higher in patients with US+/biopsy+ than in those with US+/biopsy−/SLNB+ (P < 0⋅001). Ten articles18,23,24,26,28 – 31,33,34 could not be included in this meta-analysis because of insufficient data. Seven studies18,26,28 – 31,34 did not report data on the number of nodes in these specific groups. In agreement with the meta-analysis finding, three studies23,24,33 that did report on the median number of nodes all found a higher median in the US+/biopsy+ group.
US+/biopsy+ versus US−/SLNB+ Six studies16,19,21,27,28,32 provided data on the percentage of patients with one to three nodes in these two groups. A total of 332 US+/biopsy+ and 458 US−/SLNB+ patients were identified, and the number with one to three involved nodes was 178 (53⋅6 per cent) and 319 (69⋅7 per cent) respectively. Absolute numbers and the results of the meta-analysis are shown in Table 3 and Fig. 4. In these studies, qualitative heterogeneity was observed. Risk ratios (and associated intervals) both above and below 1⋅00 are seen in the forest plot. There was no indication of publication bias. Twelve studies18,20,22 – 26,29 – 31,33,34 could not be included in this analysis because of insufficient data, although four studies23,24,33,34 that did provide some data all reported a higher median number of nodes in the US+/biopsy+ group. This heterogeneity means that no conclusion can be drawn on whether the US+/biopsy+ group had more or fewer involved nodes at ALND than the US−/SLNB+ group. At best, it can be stated that the majority of studies reporting on these two groups found more nodes in the US+/biopsy+ group. US+/biopsy−/SLNB+ versus US−/SLNB+ Six studies16,19,21,24,27,32 provided data on the number of patients with one to three positive nodes after ALND in the US+/biopsy−/SLNB+ and US−/SLNB+ groups. Absolute numbers and results of the meta-analysis are shown in Table 4 and Fig. 5. Some 42 (86 per cent) of 49 patients in the US+/biopsy−/SLNB+ group and 311 (72⋅0 per cent) of 432 patients in the US−/SLNB+ group had one to three involved nodes. Four studies16,24,27,32 did not show any difference between the two groups, indicative of a null effect. Two other studies19,21 demonstrated a contradictory effect. There was little difference between the groups in meta-analysis, and thus the observed differences could be chance findings. In support of this, no significant heterogeneity was observed © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(I 2 = 0 per cent, P = 0⋅95). Overall, the meta-analysis indicates no difference between these two groups. However, owing to the small number of included studies and numbers of patients, these results could be subject to selection bias. Discussion
Since the introduction of SLNB to stage the axilla in patients with breast cancer, effort has been made to identify patients who will benefit most from completion ALND (cALND), withholding this procedure in SLNB-negative patients. The results of the Z0011 trial and other studies8 – 10 suggest that a selected group of node-positive patients can also be treated safely without additional axillary surgery. Both local recurrence and overall survival rates are reported to be similar for patients treated with or without cALND8 – 10 . This meta-analysis demonstrates that ultrasound-guided biopsy can identify most patients with extensive nodal involvement: 56⋅0 per cent of patients in the US+/biopsy+ group had more than three affected nodes. These patients probably benefit most from additional axillary treatment. Detection of involved nodes by ultrasound-guided FNAC or CNB could also set the stage for neoadjuvant treatment, followed eventually by definitive axillary staging. Given the low probability of more than three involved nodes in US+/biopsy−/SLNB+ and US−/SLNB+ groups, additional axillary treatment in these patients could be omitted. In the present meta-analysis, the number of positive nodes was significantly higher in the US+/biopsy+ group than in the US+/biopsy−/SLNB+ group (P < 0⋅001). When US+/biopsy+ and US−/SLNB+ groups were compared, four studies16,19,27,32 found more positive nodes in the US+/biopsy+ group compared with two21,28 that found more positive nodes in the US−/SLNB+ group. However, a recent study35 , which could not be included in the meta-analysis because of missing data, reported no difference in the number of involved lymph nodes detected by FNAC or SLNB. The authors concluded that no difference in axillary disease burden was present in these groups, although an increased percentage of macrometastases was seen in the FNAC-guided group. The difference in nodal involvement observed in the present study was also found in two retrospective studies36,37 that assessed the use of axillary ultrasonography without confirmatory FNAC in the identification of patients with N2 or N3 disease. In one study37 , 6⋅7 per cent of ultrasound-negative patients were found to be N2 or N3 after ALND. The other study36 reported that 2⋅6 per cent of ultrasound-negative patients had N2 or N3 disease www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
after ALND, and 83⋅3 per cent of all patients with N2–3 disease were found to be positive on ultrasound imaging, comprising 28 per cent of all ultrasound-positive patients. In a meta-analysis15 investigating the accuracy and value of ultrasound-guided needle biopsy of axillary nodes in patients with breast cancer, the median sensitivity of ultrasonography alone was 61⋅4 per cent with a specificity of 82⋅0 per cent. Calculation of median sensitivity and specificity was performed in order to appreciate the accuracy of ultrasound imaging in the detection of any metastasis, not only N2 or N3 disease. It is reasonable to believe that patients with minimal nodal involvement are more likely to be missed by axillary ultrasonography, hence contributing to a lower than desired sensitivity. The possible clinical implications of the results of the present meta-analysis and the above studies are acknowledged in the SOUND (Sentinel node versus Observation after axillary UltrasouND) trial38 . In this prospective multicentre study, patients with negative axillary nodes on ultrasound imaging and T1 breast cancer, suitable for breast-conserving therapy, are randomized to SLNB with or without ALND or to no further axillary staging. In the present study, no difference was found in the number of affected nodes between US+/biopsy−/SLNB+ and US−/SLNB+ groups. This in contrast to what was expected, as nodes suspicious on ultrasound imaging are thought to be indicative of more marked nodal involvement36,37 . Because of the limited number of studies in this subanalysis, and the relatively small numbers of patients included, selection bias cannot be excluded. The results of many single-centre studies and the meta-analysis15 of the accuracy and value of ultrasound-guided techniques to stage the axilla in patients with breast cancer have contributed to the incorporation of axillary ultrasound imaging followed by ultrasound-guided biopsy in patients with radiologically suspicious nodes in British NICE12 and Dutch13 breast cancer guidelines. However, the National Comprehensive Cancer Network guideline39 does not advocate routine axillary ultrasonography in clinically node-positive patients. Axillary ultrasonography and ultrasound-guided biopsy in patients with suspicious nodes on ultrasound imaging is advocated only if neoadjuvant systemic treatment is being considered39 . Given that only modest effort in time and resources40 is needed to implement standard axillary ultrasound imaging – triaging approximately 15–20 per cent of node-negative patients directly to ALND without SLNB15 – the standard implementation of this technique could be of great value in the routine work-up of clinically node-negative patients.
Other non-invasive imaging modalities for staging of the axilla are unlikely to be incorporated in routine work-up in the near future. Axillary MRI using gadolinium-based dynamic contrast enhancement is currently being investigated41 to assess the axilla. However, although developments are promising, sensitivity and specificity values for the detection of metastatic axillary lymph nodes are currently low41 . Probably more promising in the detection of axillary involvement is [18 F]fluorodeoxyglucose (FDG)-PET–CT. A meta-analysis42 showed a pooled median sensitivity of 63 per cent and specificity of 94 per cent, indicating that this method is of similar value to axillary ultrasonography and ultrasound-guided biopsy techniques. Given its increasing resolution and decreasing costs, FDG-PET–CT will become an increasingly important imaging modality in breast cancer, but is currently not recommended for routine evaluation of the clinically node-negative axilla42 . A clear limitation of the present review is that only 18 of 64 articles could be included. Although effort was made to contact corresponding authors when data were missing, 14 potentially eligible articles had to be excluded. Another reason for exclusion was the need for information on the number of involved nodes in patients with positive ultrasound-guided biopsy findings. In addition, the quality of the articles varied, with QUADAS scores ranging from 8 to 12 on the 14-item score, although 12 of 18 studies scored 10 or more points, demonstrating high quality. The study design of a considerable number of included studies was retrospective and inclusion was non-consecutive, increasing the likelihood of bias. This meta-analysis shows that patients with breast cancer in whom axillary metastases are detected by ultrasound-guided biopsy have significantly more involved nodes than SLNB-positive patients. These patients with more involved nodes probably benefit most from further axillary treatment. Patients with no suspicious nodes on ultrasound imaging and those with a negative ultrasound-guided biopsy could possibly be spared the sentinel lymph node procedure. This hypothesis is currently being studied in the SOUND and INSEMA (Intergroup Sentinel Mamma) trials, in which patients with negative axillary findings on ultrasound imaging and T1 breast cancer, suitable for breast-conserving surgery, are randomized to SLNB with or without ALND versus no further axillary staging38,43 .
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
Disclosure
The authors declare no conflict of interest. BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
References 1 Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24 740 breast cancer cases. Cancer 1989; 63: 181–187. 2 Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH, Murphy GP. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 1980; 45: 2917–2924. 3 Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 2010; 11: 927–933. 4 Veronesi U, Viale G, Paganelli G, Zurrida S, Luini A, Galimberti V et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg 2010; 251: 595–600. 5 Schiffman SC, McMasters KM, Scoggins CR, Martin RC, Chagpar AB. Lymph node ratio: a proposed refinement of current axillary staging in breast cancer patients. J Am Coll Surg 2011; 213: 45–52. 6 Vinh-Hung V, Verkooijen HM, Fioretta G, Neyroud-Caspar I, Rapiti E, Vlastos G et al. Lymph node ratio as an alternative to pN staging in node-positive breast cancer. J Clin Oncol 2009; 27: 1062–1068. 7 Dings PJ, Elferink MA, Strobbe LJ, de Wilt JH. The prognostic value of lymph node ratio in node-positive breast cancer: a Dutch nationwide population-based study. Ann Surg Oncol 2013; 20: 2607–2614. 8 Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM 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: 426–432. 9 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: a randomized clinical trial. JAMA 2011; 305: 569–575. 10 Francissen CM, Dings PJ, van Dalen T, Strobbe LJ, van Laarhoven HW, de Wilt JH. Axillary recurrence after a tumor-positive sentinel lymph node biopsy without axillary treatment: a review of the literature. Ann Surg Oncol 2012; 19: 4140–4149. 11 Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P 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: 297–305. 12 Harnett A, Smallwood J, Titshall V, Champion A; Guideline Development Group. Diagnosis and treatment of early breast cancer, including locally advanced disease – summary of NICE guidance. BMJ 2009; 338: b438.
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
13 Comprehensive Cancer Centre, The Netherlands. National Guideline Breast Cancer 2⋅0; 2012. http://www.oncoline.nl/ mammacarcinoom [accessed 16 January 2014]. 14 Vassallo P, Wernecke K, Roos N, Peters PE. Differentiation of benign from malignant superficial lymphadenopathy: the role of high-resolution US. Radiology 1992; 183: 215–220. 15 Houssami N, Ciatto S, Turner RM, Cody HS III, Macaskill P. Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Ann Surg 2011; 254: 243–251. 16 van Wely BJ, de Wilt JH, Schout PJ, Kooistra B, Wauters CA, Venderinck D et al. Ultrasound-guided fine-needle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement. Breast Cancer Res Treat 2013; 140: 113–118. 17 Whiting P, Rutjes AW, Dinnes J, Reitsma J, Bossuyt PM, Kleijnen J et al. Development and validation of methods for assessing the quality of diagnostic accuracy studies. Health Technol Assess 2004; 8: iii, 1–234. 18 Bonnema J, van Geel AN, van Ooijen B, Mali SP, Tjiam SL, Henzen-Logmans SC et al. Ultrasound-guided aspiration biopsy for detection of nonpalpable axillary node metastases in breast cancer patients: new diagnostic method. World J Surg 1997; 21: 270–274. 19 Damera A, Evans AJ, Cornford EJ, Wilson AR, Burrell HC, James JJ et al. Diagnosis of axillary nodal metastases by ultrasound-guided core biopsy in primary operable breast cancer. Br J Cancer 2003; 89: 1310–1313. 20 Kuenen-Boumeester V, Menke-Pluymers M, de Kanter AY, Obdeijn IM, Urich D, Van Der Kwast TH. Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure. Eur J Cancer 2003; 39: 170–174. 21 Lemos S, Dias M, Gonçalo M, Pinto E, Fernandes G, Oliveira C et al. Detection of axillary metastases in breast cancer patients using ultrasound and colour Doppler combined with fine needle aspiration cytology. Eur J Gynaecol Oncol 2005; 26: 165–166. 22 de Kanter AY, Menke-Pluijmers MB, Henzen-Logmans SC, van Geel AN, van Eijck CJ, Wiggers T et al. Reasons for failure to identify positive sentinel nodes in breast cancer patients with significant nodal involvement. Eur J Surg Oncol 2006; 32: 498–501. 23 van Rijk MC, Deurloo EE, Nieweg OE, Gilhuijs KG, Peterse JL, Rutgers EJ et al. Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. Ann Surg Oncol 2006; 13: 31–35. 24 Davis JT, Brill YM, Simmons S, Sachleben BC, Cibull ML, McGrath P et al. Ultrasound-guided fine-needle aspiration of clinically negative lymph nodes versus sentinel node mapping in patients at high risk for axillary metastasis. Ann Surg Oncol 2006; 13: 1545–1552. 25 Ciatto S, Brancato B, Risso G, Ambrogetti D, Bulgaresi P, Maddau C et al. Accuracy of fine needle aspiration cytology
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
26
27
28
29
30
31
32
33
34
(FNAC) of axillary lymph nodes as a triage test in breast cancer staging. Breast Cancer Res Treat 2007; 103: 85–91. Nori J, Vanzi E, Bazzocchi M, Bufalini FN, Distante V, Branconi F et al. Role of axillary ultrasound examination in the selection of breast cancer patients for sentinel node biopsy. Am J Surg 2007; 193: 16–20. Hinson JL, McGrath P, Moore A, Davis JT, Brill YM, Samoilova E et al. The critical role of axillary ultrasound and aspiration biopsy in the management of breast cancer patients with clinically negative axilla. Ann Surg Oncol 2008; 15: 250–255. Holwitt DM, Swatske ME, Gillanders WE, Monsees BS, Gao F, Aft RL et al. Scientific Presentation Award: The combination of axillary ultrasound and ultrasound-guided biopsy is an accurate predictor of axillary stage in clinically node-negative breast cancer patients. Am J Surg 2008; 196: 477–482. Tahir M, Osman KA, Shabbir J, Rogers C, Suarez R, Reynolds T et al. Preoperative axillary staging in breast cancer – saving time and resources. Breast J 2008; 14: 369–371. Swinson C, Ravichandran D, Nayagam M, Allen S. Ultrasound and fine needle aspiration cytology of the axilla in the pre-operative identification of axillary nodal involvement in breast cancer. Eur J Surg Oncol 2009; 35: 1152–1157. Rao R, Lilley L, Andrews V, Radford L, Ulissey M. Axillary staging by percutaneous biopsy: sensitivity of fine-needle aspiration versus core needle biopsy. Ann Surg Oncol 2009; 16: 1170–1175. Schiettecatte A, Bourgain C, Breucq C, Buls N, De Wilde V, de Mey J. Initial axillary staging of breast cancer using ultrasound-guided fine needle aspiration: a liquid-based cytology study. Cytopathology 2011; 22: 30–35. García Fernández A, Fraile M, Giménez N, Reñe A, Torras M, Canales L et al. Use of axillary ultrasound, ultrasound-fine needle aspiration biopsy and magnetic resonance imaging in the preoperative triage of breast cancer patients considered for sentinel node biopsy. Ultrasound Med Biol 2011; 37: 16–22. Solon JG, Power C, Al-Azawi D, Duke D, Hill AD. Ultrasound-guided core biopsy: an effective method of
35
36
37
38
39
40
41
42
43
detecting axillary nodal metastases. J Am Coll Surg 2012; 214: 12–17. Cools-Lartigue J, Sinclair A, Trabulsi N, Meguerditchian A, Mesurolle B, Fuhrer R et al. Preoperative axillary ultrasound and fine-needle aspiration biopsy in the diagnosis of axillary metastases in patients with breast cancer: predictors of accuracy and future implications. Ann Surg Oncol 2013; 20: 819–827. Abe H, Schacht D, Sennett CA, Newstead GM, Schmidt RA. Utility of preoperative ultrasound for predicting pN2 or higher stage axillary lymph node involvement in patients with newly diagnosed breast cancer. AJR Am J Roentgenol 2013; 200: 696–702. Neal CH, Daly CP, Nees AV, Helvie MA. Can preoperative axillary US help exclude N2 and N3 metastatic breast cancer? Radiology 2010; 257: 335–341. Gentilini O, Veronesi U. Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European Institute of Oncology of Milan (SOUND: Sentinel node vs Observation after axillary UltraSouND). Breast 2012; 21: 678–681. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, Version 3; 2012. http://www.nccn.org [accessed 8 October 2013]. Genta F, Zanon E, Camanni M, Deltetto F, Drogo M, Gallo R et al. Cost/accuracy ratio analysis in breast cancer patients undergoing ultrasound-guided fine-needle aspiration cytology, sentinel lymph node biopsy, and frozen section of node. World J Surg 2007; 31: 1155–1163. Mortellaro VE, Marshall J, Singer L, Hochwald SN, Chang M, Copeland EM et al. Magnetic resonance imaging for axillary staging in patients with breast cancer. J Magn Reson Imaging 2009; 30: 309–312. Cooper KL, Harnan S, Meng Y, Ward SE, Fitzgerald P, Papaioannou D et al. Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis. Eur J Surg Oncol 2011; 37: 187–198. Reimer T, Hartmann S, Stachs A, Gerber B. Local treatment of the axilla in early breast cancer: concepts from the National Surgical Adjuvant Breast and Bowel Project B-04 to the Planned Intergroup Sentinel Mamma Trial. Breast Care 2014; 9: 87–95.
Supporting information
Additional supporting information may be found in the online version of this article: Table S1 Literature search details (Word document)
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
Meta-analysis of ultrasound-guided biopsy of suspicious axillary lymph nodes in the selection of patients with extensive axillary tumour burden in breast cancer B. J. van Wely1 , J. H. W. de Wilt2 , C. Francissen4 , S. Teerenstra3 and L. J. A. Strobbe1 1 Department
of Surgery, Canisius Wilhelmina Hospital, and 2 Department of Surgery and 3 Section of Biostatistics, Department of Health Evidence, Radboud University Medical Centre, Nijmegen, and 4 Department of Surgery, Geldersche Vallei Hospital, Ede, The Netherlands Correspondence to: Dr B. J. van Wely, B62, Department of Surgery, Canisius Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands (e-mail: [email protected])
Background: Recent studies show that not all patients with breast cancer and positive axillary lymph
nodes need additional axillary surgery. A systematic review and meta-analysis of the literature was performed to test the hypothesis that ultrasound-guided biopsy of suspicious nodes can be a useful tool to identify patients with extensive axillary tumour burden. Methods: PubMed and Embase were searched to identify articles reporting on ultrasound-guided techniques to stage the axilla of patients with breast cancer. The emphasis was to study the number of positive nodes found after axillary lymph node dissection (ALND) following a positive ultrasound-guided biopsy or a positive sentinel lymph node biopsy (SLNB). Information regarding the number of positive nodes thus had to be available. Results were tested for heterogeneity and a meta-analysis was performed. Results: A total of 894 articles were identified, and 115 were selected based on title and abstract information by two independent reviewers. After extensive review, 18 articles were eligible for analysis. Eight studies reported sufficient data to perform a meta-analysis comparing 532 patients with a positive ultrasound-guided biopsy with 248 patients with a negative ultrasound-guided biopsy but a positive SLNB. The number of involved nodes was significantly higher in patients in whom axillary metastasis was detected by ultrasound-guided biopsy (P < 0⋅001). No heterogeneity in the observed effect was found (I 2 = 22 per cent, P = 0⋅26). Conclusion: Patients with breast cancer in whom axillary metastases are detected by ultrasound-guided biopsy have significantly more involved nodes than SLNB-positive patients. This finding enables further preoperative tailoring of axillary treatment in breast cancer. Presented to the 32nd Congress of the European Society of Surgical Oncology, Valencia, Spain, September 2012 Paper accepted 1 September 2014 Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9663
Introduction
In breast cancer, axillary lymph node involvement is an important prognostic factor. Patients without axillary involvement have a significantly better prognosis than patients with N1–3 disease1,2 . Before the introduction of sentinel lymph node biopsy (SLNB), elective axillary lymph node dissection (ALND) was performed in all patients. After the introduction and validation of SLNB to stage the axilla, ALND was omitted in patients with a negative SLNB3,4 . In patients with a positive SLNB, additional ALND is usually performed, and the number of positive nodes found by the pathologist as well as the © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
total number of nodes retrieved during ALND (positive and negative) have clinical importance. The correlation between the number of positive nodes found and the number of nodes retrieved is known as the lymph node ratio (LNR). Several publications have established that the LNR is also a strong prognostic factor – even more predictive of outcome than N category5 – 7 . However, with the effective systemic adjuvant treatment currently available, the need for ALND in all node-positive patients is under debate. The Z0011 trial8,9 reported good locoregional control and overall survival rates in patients with limited tumour burden (fewer than 3 positive nodes) who did not undergo ALND. Although this study was BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
underpowered, the results have been confirmed by several other studies10,11 . Thus, the preoperative diagnostic pathway for patients with newly diagnosed breast cancer should ideally have a diagnostic tool to differentiate between patients with limited (3 or fewer positive nodes, or N1) and more extensive (more than 3 positive nodes, or N2) axillary tumour burden. Routine axillary ultrasonography in case of a malignant breast lesion is advocated by the UK National Institute of Care and Health Excellence (NICE)12 and Dutch13 breast cancer guidelines. In the case of ultrasonographically suspicious lymph nodes (defined as nodes that are rounder, have an asymmetrical cortex, are thicker than 3 mm or have lost the hyperechoic hilum14 ), ultrasound-guided core needle biopsy (CNB) or fine-needle aspiration cytology (FNAC) should be used to detect axillary metastasis before surgery. When pathological analysis confirms metastasis in the lymph node, these patients do not have to undergo SLNB and can proceed directly to ALND. The sensitivity and specificity of ultrasound-guided techniques to stage the axilla have been reported by many authors. A recent meta-analysis15 on the subject revealed median sensitivity of 79⋅6 per cent and median specificity of 98⋅3 per cent. A recent analysis16 of the prospective database in the breast cancer unit at Canisius Wilhelmina Hospital, Nijmegen, The Netherlands, showed significantly more involved nodes in patients with positive ultrasound-guided FNAC than in patients in whom axillary involvement was diagnosed by SLNB (for both ultrasonographically suspicious and non-suspicious nodes). This finding led to the hypothesis that ultrasound-guided biopsy techniques might be a useful diagnostic tool to differentiate between more or less extensive axillary tumour burden in patients with breast cancer. To test this hypothesis, a systematic review of the literature was performed and a meta-analysis conducted.
Review inclusion and exclusion criteria Articles had to be published in English. The aim of the review was to identify original articles that reported on a cohort of patients with breast cancer in whom ultrasound-guided biopsy techniques were used to stage the axilla. In studies that report on the number of positive nodes after ultrasound-guided biopsy, three distinctive groups of node-positive patients can be identified: patients who have ALND after a positive ultrasound-guided biopsy of suspicious nodes (US+/biopsy+); patients with a negative ultrasound-guided biopsy of ultrasonographically suspicious nodes but a positive SLNB (US+/biopsy−/SLNB+); and patients with no ultrasonographically suspicious nodes who have a positive SLNB (US−/SLNB+) (Fig. 1). To be eligible for review, articles should have reported on the number of positive nodes found at ALND after positive ultrasound-guided biopsy and positive SLNB findings. Information for at least two of the subgroups mentioned above had to be available. When not all information on positive nodes was available, effort was made to calculate this from the data provided. Where the data were insufficient, the corresponding author was contacted. Failure to meet the above criteria resulted in exclusion from the review. Because the main interest was to evaluate ultrasound-guided techniques used to stage the axilla of all patients with breast cancer, articles that reported only
All patients with breast cancer Ultrasound imaging of axilla
Suspicious nodes
No suspicious nodes
Ultrasound-guided biopsy
Methods
Literature search A literature search was performed in PubMed and Embase. Search terms used were ‘Ultrasound’, ‘Breast Cancer’ and ‘Axillary’; literature search details are shown in Table S1 (supporting information). To complete the search, related articles were searched, as well as references within selected articles. Two reviewers independently selected potentially relevant papers based on title and abstract. Discrepancies between the reviewers were resolved by consensus. The literature search was last updated in September 2013. © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Positive
Negative
SLNB
Positive
Negative
SLNB
Positive
Negative
Axillary lymph node dissection
Flow chart showing how patients could be allocated to axillary lymph node dissection in the included studies. SLNB, sentinel lymph node biopsy
Fig. 1
www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
Records identified through PubMed search n = 852
Records identified through Embase search n = 884
Records after duplicates removed n = 894 Records excluded (did not meet inclusion criteria) n = 779 Title and abstract selection n = 115 Articles excluded (did not meet exclusion criteria) n = 51 Full-text articles assessed for eligibility n = 64 Full-text articles excluded n = 46 No. of nodes after ALND not stated n = 40 No response from author n = 6 Articles accepted for review n = 18 Fig. 2
PRISMA flow diagram for the study. ALND, axillary lymph node dissection
Table 1
Articles included in the review Baseline study results
Reference
Year
QUADAS score (0–14)
Bonnema et al.18 Damera et al.19 Kuenen-Boumeester et al.20 Lemos et al.21 de Kanter et al.22 van Rijk et al.23 Davis et al.24 Ciatto et al.25 Nori et al.26 Hinson et al.27 Holwitt et al.28 Tahir et al.29 Swinson et al.30 Rao et al.31 Schiettecatte et al.32 García Fernández et al.33 Solon et al.34 van Wely et al.16
1997 2003 2003 2005 2006 2006 2006 2007 2007 2008 2008 2008 2009 2009 2010 2011 2012 2013
11 12 12 8 9 12 10 10 9 9 10 8 11 9 10 12 11 12
Total
No. of patients
No. of US+ patients
150 103 183 40 161 732 37 476 132 112 256 38 369 47 148 520 445 1448
93 (62⋅0) 54 (52⋅4) 183 (100) 10 (25) n.s. 176 (24⋅0) 22 (59) 476 (100) 31 (23⋅5) 61 (54⋅5) 110 (43⋅0) 38 (100) 114 (30⋅9) 47 (100) 58 (39⋅2) 96 (18⋅5) 121 (27⋅2) 234 (16⋅2)§
5397
Node-positive patients and detection method used
No. of ultrasound-guided biopsies 81 54 183 10 161 176 22 488 14† 61 110 38 111 47 55 96 121 234 2062
No. of node-positive patients 62 (41⋅3) 46 (44⋅7) 85 (46⋅4) 11 (28) 79 (49⋅1) 271 (37⋅0) n.s. 308 (64⋅7) 42 (31⋅8) 58 (51⋅8) 113 (44⋅1) 17 (45) 116 (31⋅4) 38 (81) 65 (43⋅9) 177 (34⋅0) 210 (47⋅2) 572 (39⋅5)§
US+/ US+/biopsy−/ biopsy+ * SLNB+
US−/ SLNB+
39 27 40 (3) 6 31 59 (1) 15 206 (7) 11 34 74 8 39 30 34 76 110 157
10 8 48 2 48 36 3 109 1 10 9 9 12 8 7 8 0 19
13 11 n.s. 3 n.s. 177 4 n.s. 23‡ 14 30 n.s. 65 n.s. 24 93 100 376
996
347
933
Values in parentheses are percentages unless indicated otherwise; *values in parentheses are number of false-positive biopsies. †Seventeen patients with suspicious nodes on initial ultrasound imaging (US+) did not undergo ultrasound-guided biopsy; ‡data were missing for seven node-positive patients; §35 patients were excluded because of indifferent findings on fine-needle aspiration cytology, 20 of whom were node-positive. biopsy+, Positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; n.s., not stated.
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
Table 2 Summary of studies included in meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with a negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy US+/biopsy+
US+/biopsy−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Ciatto et Damera et al.19 de Kanter et al.22 Hinson et al.27 Kuenen-Boumeester et al.20 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
206 27 31 34 37 6 34 157
89 (43.2) 9 (33) 15 (48) 15 (44) 17 (46) 5 (83) 15 (44) 69 (43⋅9)
117 (56⋅8) 18 (67) 16 (52) 19 (56) 20 (54) 1 (17) 19 (56) 88 (56⋅1)
109 8 48 10 45 2 7 19
71 (65⋅1) 7 (88) 38 (79) 10 (100) 41 (91) 2 (100) 7 (100) 13 (68)
38 (34⋅9) 1 (12) 10 (21) 0 (0) 4 (9) 0 (0) 0 (0) 6 (32)
Total
532
234 (44⋅0)
298 (56⋅0)
248
189 (76⋅2)
59 (23⋅8)
Reference al.25
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy. No. of patients with 1–3 nodes Reference al.25
Ciatto et Damera et al.19 de Kanter et al.22 Hinson et al.27 Kuenen-Boumeester et al.20 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16 Total
US+/biopsy+ US+/biopsy–/SLNB+ Weight (%)
Risk ratio
89 of 206 9 of 27 15 of 31 15 of 34 17 of 37 5 of 6 15 of 34 69 of 157
71 of 109 7 of 8 38 of 48 10 of 10 41 of 45 2 of 2 7 of 7 13 of 19
27·6 5·8 11·8 11·7 13·4 5·1 10·8 13·9
0·66 (0·54, 0·82) 0·38 (0·21, 0·69) 0·61 (0·41, 0·90) 0·46 (0·31, 0·69) 0·50 (0·35, 0·72) 0·94 (0·50, 1·78) 0·47 (0·31, 0·71) 0·64 (0·45, 0·91)
234 of 532
189 of 248
100·0
0·57 (0·49, 0·67)
Heterogeneity: τ2 = 0·01; χ2 = 8·95, 7 d.f., P = 0·26; I2 = 22% Test for overall effect: Z = 7·22, P < 0·001
Risk ratio
0·01
0·1 More nodes in US+/biopsy+
1
10
100
More nodes in US+/biopsy–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with a negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy
Fig. 3
on patients with a high risk of axillary metastasis were excluded.
Study quality assessment The QUADAS tool, a validated quality assessment tool for diagnostic accuracy studies, was used to assess the quality of included articles17 . The checklist contains 14 items that can be scored for each study; each characteristic mentioned or available in the article scores one point; the maximum score is thus 14.
not be calculated. In addition, it was not possible to distinguish between one or two and more than two involved nodes, as defined in the Z0011 trial8,9 . The number of patients with N1 or N2 disease was compared between the different subgroups (US+/biopsy+ versus US+/biopsy−/ SLNB+, US+/biopsy+ versus US−/SLNB+, and US+/ biopsy−/SLNB+ versus US−/SLNB+). In the metaanalysis, the proportions of node-positive patients with one to three positive nodes in the various groups were compared. However, in the interpretation of the results, the number of patients with more than three involved nodes is of particular interest.
Number of positive nodes involved Because no source data on the total number of nodes were available, only the number of patients with one to three (N1 disease) or more than three (N2 disease) positive nodes could be documented. For this reason, the LNR could © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
Statistical analysis To compare the number of positive nodes between the three groups, a random-effects meta-analysis with Cochrane–Mantel–Haenszel weighting was performed www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
Summary of studies included in meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy
Table 3
US+/biopsy+
US−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Damera et Hinson et al.27 Holwitt et al.28 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
27 34 74 6 34 157
9 (33) 15 (44) 65 (88) 5 (83) 15 (44) 69 (43⋅9)
18 (67) 19 (46) 9 (12) 1 (17) 19 (46) 88 (56⋅1)
11 14 30 3 24 376
11 (100) 14 (100) 12 (40) 2 (67) 24 (100) 256 (68⋅1)
0 (0) 0 (0) 18 (60) 1 (33) 0 (0) 120 (31⋅9)
Total
332
178 (53⋅6)
154 (46⋅4)
458
319 (69⋅7)
139 (30⋅3)
Reference al.19
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; US−, no suspicious nodes on initial ultrasound imaging; SLNB+, positive nodes on sentinel lymph node biopsy.
No. of patients with 1–3 nodes Reference
US+/biopsy+
US–/SLNB+
Weight (%)
Risk ratio
9 of 27 15 of 34 65 of 74 5 of 6 15 of 34 69 of 157
11 of 11 14 of 14 12 of 30 2 of 3 24 of 24 256 of 376
16·1 17·7 17·0 12·0 17·8 19·4
0·35 (0·21, 0·60) 0·46 (0·31. 0·67) 2·20 (1·41, 3·43) 1·25 (0·52, 3·00) 0·45 (0·31, 0·66) 0·65 (0·53, 0·78)
178 of 332
319 of 458
100·0
0·69 (0·43, 1·12)
Damera et al.19 Hinson et al.27 Holwitt et al.28 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16 Total
Heterogeneity: τ2 = 0·30; χ2 = 44·09, 5 d.f., P < 0·001; I2 = 89% Test for overall effect: Z = 1·51, P = 0·13
Risk ratio
0·01
0·1
More nodes in US+/biopsy+
1
10
100
More nodes in US–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with a positive ultrasound-guided biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy+, positive nodes on ultrasound-guided biopsy; US−, no suspicious nodes on initial ultrasound imaging; SLNB+, positive nodes on sentinel lymph node biopsy
Fig. 4
of the percentage of patients with one to three positive nodes, using Review Manager (RevMan) version 5.0 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). As a summary measure, the ratio of these percentages was used. Studies were included in the meta-analysis if this percentage was present in, or could be estimated from, the reported results. In addition, the results of the meta-analysis were compared qualitatively with findings from other studies (not included in the meta-analysis because of missing data), provided these studies reported on both groups. Heterogeneity was tested for, and a funnel plot was used to test for publication bias. P < 0⋅050 was considered statistically significant.
eligible articles. References from the two searches were combined, resulting in 894 articles that were available for title and abstract reviewing. This process led to the exclusion of 779 articles that did not meet inclusion criteria. Following extensive review of 115 eligible articles, a further 51 articles were excluded because inclusion criteria were not met. Sixty-four articles reported on ultrasound-guided techniques to stage the axilla, but 46 of these did not report all data necessary for inclusion, or reported on a specific subset of patients, thereby introducing a selection bias. These 46 articles were excluded from further review. A total of 18 articles met the inclusion criteria and were eligible for review and meta-analysis (Fig. 2). Detailed information on the reviewed articles16,18 – 34 is displayed in Table 1.
Results
Literature search
Data analysis
A total of 852 articles were found in the PubMed database search, and the Embase search resulted in 884 potentially
Of the 18 articles selected for review, ten provided sufficient data on the number of patients with N1 and N2
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
Table 4 Summary of studies included in meta-analysis comparing patients with negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy US+/biopsy−/SLNB+
US−/SLNB+
No. of patients
1–3 nodes
> 3 nodes
No. of patients
1–3 nodes
> 3 nodes
Damera et Davis et al.24 Hinson et al.27 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
8 3 10 2 7 19
7 (88) 3 (100) 10 (100) 2 (100) 7 (100) 13 (68)
1 (12) 0 (0) 0 (0) 0 (0) 0 (0) 6 (32)
11 4 14 3 24 376
11 (100) 4 (100) 14 (100) 2 (67) 24 (100) 256 (68⋅1)
0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 120 (31⋅9)
Total
49
42 (86)
7 (14)
432
311 (72⋅0)
121 (28⋅0)
Reference al.19
Values in parentheses are percentages. US+, suspicious nodes on initial ultrasound imaging; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; US−, no suspicious nodes on initial ultrasound imaging.
No. of patients with 1–3 nodes Reference Damera et al.19 Davis et al.24 Hinson et al.27 Lemos et al.21 Schiettecatte et al.32 van Wely et al.16
US+/biopsy–/SLNB+ US–/SLNB+ 7 of 8 3 of 3 10 of 10 2 of 2 7 of 7 13 of 19
11 of 11 4 of 4 14 of 14 2 of 3 24 of 24 256 of 376
42 of 49 311 of 432 Total Heterogeneity: τ2 = 0·00; χ2 = 1·10, 5 d.f., P = 0·95; I2 = 0% Test for overall effect: Z = 0·20, P = 0·84
Weight (%)
Risk ratio
10·8 4·8 41·9 1·3 30·4 10·9
0·87 (0·63, 1·19) 1·00 (0·62, 1·60) 1·00 (0·85, 1·17) 1·33 (0·54, 3·32) 1·00 (0·83, 1·21) 1·00 (0·73, 1·37)
100·0
0·99 (0·89, 1·10)
Risk ratio
0·5
0·7
1
More nodes in US+/biopsy–/SLNB+
1·5
2
More nodes in US–/SLNB+
Forest plot illustrating results of a meta-analysis comparing patients with negative ultrasound-guided biopsy but a positive sentinel lymph node biopsy with patients with no suspicious nodes on ultrasound imaging but a positive sentinel lymph node biopsy. Risk ratios with 95 per cent c.i. were calculated using a Cochrane–Mantel–Haenszel random-effects model. US+, suspicious nodes on initial ultrasound imaging; biopsy−, negative nodes on ultrasound-guided biopsy; SLNB+, positive nodes on sentinel lymph node biopsy; US−, no suspicious nodes on initial ultrasound imaging
Fig. 5
disease in at least two groups. The other eight articles provided information on the number of involved nodes, but could not be included in the meta-analysis because only the median number of positive nodes was provided. Only a limited number of articles reported on the number of patients in whom only micrometastasis was detected. There were two studies in the US+/biopsy−/ SLNB+ group; the number of node-positive patients with only micrometastases was three of three24 and five of seven32 . In the US−/SLNB+ group, three studies reported on micrometastasis: 14 of 24 patients32 , 20 of 2326 and 20 per cent (absolute numbers not given)33 had only micrometastasis. The results of the meta-analysis were compared qualitatively to findings in these studies, provided that the studies reported on both groups.
US+/biopsy+ versus US+/biopsy−/SLNB+ Eight studies16,19 – 22,25,27,32 provided data on the percentage of patients with one to three positive nodes found at ALND, enabling 532 patients with a positive ultrasound-guided biopsy (US+/biopsy+) to be compared with 248 patients with a negative ultrasound-guided biopsy but a positive SLNB (US+/biopsy−/SLNB+). The number of patients with one to three positive nodes was 234 (44⋅0 per cent) and 189 (76⋅2 per cent) respectively. Absolute numbers and the results of the meta-analysis are shown in Table 2 and Fig. 3. The forest plot shows consistency of the observed effect: all risk ratios were less than 1⋅00, and all but one study21 also had confidence intervals below 1⋅00. This indicates that significantly more patients in the US+/biopsy+ group had more than three involved nodes. No indication of heterogeneity was found between the studies
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
(I 2 = 22 per cent, P = 0⋅26), and the funnel plot showed no indication of publication bias. The meta-analysis thus provides strong evidence that the number of nodes is higher in patients with US+/biopsy+ than in those with US+/biopsy−/SLNB+ (P < 0⋅001). Ten articles18,23,24,26,28 – 31,33,34 could not be included in this meta-analysis because of insufficient data. Seven studies18,26,28 – 31,34 did not report data on the number of nodes in these specific groups. In agreement with the meta-analysis finding, three studies23,24,33 that did report on the median number of nodes all found a higher median in the US+/biopsy+ group.
US+/biopsy+ versus US−/SLNB+ Six studies16,19,21,27,28,32 provided data on the percentage of patients with one to three nodes in these two groups. A total of 332 US+/biopsy+ and 458 US−/SLNB+ patients were identified, and the number with one to three involved nodes was 178 (53⋅6 per cent) and 319 (69⋅7 per cent) respectively. Absolute numbers and the results of the meta-analysis are shown in Table 3 and Fig. 4. In these studies, qualitative heterogeneity was observed. Risk ratios (and associated intervals) both above and below 1⋅00 are seen in the forest plot. There was no indication of publication bias. Twelve studies18,20,22 – 26,29 – 31,33,34 could not be included in this analysis because of insufficient data, although four studies23,24,33,34 that did provide some data all reported a higher median number of nodes in the US+/biopsy+ group. This heterogeneity means that no conclusion can be drawn on whether the US+/biopsy+ group had more or fewer involved nodes at ALND than the US−/SLNB+ group. At best, it can be stated that the majority of studies reporting on these two groups found more nodes in the US+/biopsy+ group. US+/biopsy−/SLNB+ versus US−/SLNB+ Six studies16,19,21,24,27,32 provided data on the number of patients with one to three positive nodes after ALND in the US+/biopsy−/SLNB+ and US−/SLNB+ groups. Absolute numbers and results of the meta-analysis are shown in Table 4 and Fig. 5. Some 42 (86 per cent) of 49 patients in the US+/biopsy−/SLNB+ group and 311 (72⋅0 per cent) of 432 patients in the US−/SLNB+ group had one to three involved nodes. Four studies16,24,27,32 did not show any difference between the two groups, indicative of a null effect. Two other studies19,21 demonstrated a contradictory effect. There was little difference between the groups in meta-analysis, and thus the observed differences could be chance findings. In support of this, no significant heterogeneity was observed © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
(I 2 = 0 per cent, P = 0⋅95). Overall, the meta-analysis indicates no difference between these two groups. However, owing to the small number of included studies and numbers of patients, these results could be subject to selection bias. Discussion
Since the introduction of SLNB to stage the axilla in patients with breast cancer, effort has been made to identify patients who will benefit most from completion ALND (cALND), withholding this procedure in SLNB-negative patients. The results of the Z0011 trial and other studies8 – 10 suggest that a selected group of node-positive patients can also be treated safely without additional axillary surgery. Both local recurrence and overall survival rates are reported to be similar for patients treated with or without cALND8 – 10 . This meta-analysis demonstrates that ultrasound-guided biopsy can identify most patients with extensive nodal involvement: 56⋅0 per cent of patients in the US+/biopsy+ group had more than three affected nodes. These patients probably benefit most from additional axillary treatment. Detection of involved nodes by ultrasound-guided FNAC or CNB could also set the stage for neoadjuvant treatment, followed eventually by definitive axillary staging. Given the low probability of more than three involved nodes in US+/biopsy−/SLNB+ and US−/SLNB+ groups, additional axillary treatment in these patients could be omitted. In the present meta-analysis, the number of positive nodes was significantly higher in the US+/biopsy+ group than in the US+/biopsy−/SLNB+ group (P < 0⋅001). When US+/biopsy+ and US−/SLNB+ groups were compared, four studies16,19,27,32 found more positive nodes in the US+/biopsy+ group compared with two21,28 that found more positive nodes in the US−/SLNB+ group. However, a recent study35 , which could not be included in the meta-analysis because of missing data, reported no difference in the number of involved lymph nodes detected by FNAC or SLNB. The authors concluded that no difference in axillary disease burden was present in these groups, although an increased percentage of macrometastases was seen in the FNAC-guided group. The difference in nodal involvement observed in the present study was also found in two retrospective studies36,37 that assessed the use of axillary ultrasonography without confirmatory FNAC in the identification of patients with N2 or N3 disease. In one study37 , 6⋅7 per cent of ultrasound-negative patients were found to be N2 or N3 after ALND. The other study36 reported that 2⋅6 per cent of ultrasound-negative patients had N2 or N3 disease www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
after ALND, and 83⋅3 per cent of all patients with N2–3 disease were found to be positive on ultrasound imaging, comprising 28 per cent of all ultrasound-positive patients. In a meta-analysis15 investigating the accuracy and value of ultrasound-guided needle biopsy of axillary nodes in patients with breast cancer, the median sensitivity of ultrasonography alone was 61⋅4 per cent with a specificity of 82⋅0 per cent. Calculation of median sensitivity and specificity was performed in order to appreciate the accuracy of ultrasound imaging in the detection of any metastasis, not only N2 or N3 disease. It is reasonable to believe that patients with minimal nodal involvement are more likely to be missed by axillary ultrasonography, hence contributing to a lower than desired sensitivity. The possible clinical implications of the results of the present meta-analysis and the above studies are acknowledged in the SOUND (Sentinel node versus Observation after axillary UltrasouND) trial38 . In this prospective multicentre study, patients with negative axillary nodes on ultrasound imaging and T1 breast cancer, suitable for breast-conserving therapy, are randomized to SLNB with or without ALND or to no further axillary staging. In the present study, no difference was found in the number of affected nodes between US+/biopsy−/SLNB+ and US−/SLNB+ groups. This in contrast to what was expected, as nodes suspicious on ultrasound imaging are thought to be indicative of more marked nodal involvement36,37 . Because of the limited number of studies in this subanalysis, and the relatively small numbers of patients included, selection bias cannot be excluded. The results of many single-centre studies and the meta-analysis15 of the accuracy and value of ultrasound-guided techniques to stage the axilla in patients with breast cancer have contributed to the incorporation of axillary ultrasound imaging followed by ultrasound-guided biopsy in patients with radiologically suspicious nodes in British NICE12 and Dutch13 breast cancer guidelines. However, the National Comprehensive Cancer Network guideline39 does not advocate routine axillary ultrasonography in clinically node-positive patients. Axillary ultrasonography and ultrasound-guided biopsy in patients with suspicious nodes on ultrasound imaging is advocated only if neoadjuvant systemic treatment is being considered39 . Given that only modest effort in time and resources40 is needed to implement standard axillary ultrasound imaging – triaging approximately 15–20 per cent of node-negative patients directly to ALND without SLNB15 – the standard implementation of this technique could be of great value in the routine work-up of clinically node-negative patients.
Other non-invasive imaging modalities for staging of the axilla are unlikely to be incorporated in routine work-up in the near future. Axillary MRI using gadolinium-based dynamic contrast enhancement is currently being investigated41 to assess the axilla. However, although developments are promising, sensitivity and specificity values for the detection of metastatic axillary lymph nodes are currently low41 . Probably more promising in the detection of axillary involvement is [18 F]fluorodeoxyglucose (FDG)-PET–CT. A meta-analysis42 showed a pooled median sensitivity of 63 per cent and specificity of 94 per cent, indicating that this method is of similar value to axillary ultrasonography and ultrasound-guided biopsy techniques. Given its increasing resolution and decreasing costs, FDG-PET–CT will become an increasingly important imaging modality in breast cancer, but is currently not recommended for routine evaluation of the clinically node-negative axilla42 . A clear limitation of the present review is that only 18 of 64 articles could be included. Although effort was made to contact corresponding authors when data were missing, 14 potentially eligible articles had to be excluded. Another reason for exclusion was the need for information on the number of involved nodes in patients with positive ultrasound-guided biopsy findings. In addition, the quality of the articles varied, with QUADAS scores ranging from 8 to 12 on the 14-item score, although 12 of 18 studies scored 10 or more points, demonstrating high quality. The study design of a considerable number of included studies was retrospective and inclusion was non-consecutive, increasing the likelihood of bias. This meta-analysis shows that patients with breast cancer in whom axillary metastases are detected by ultrasound-guided biopsy have significantly more involved nodes than SLNB-positive patients. These patients with more involved nodes probably benefit most from further axillary treatment. Patients with no suspicious nodes on ultrasound imaging and those with a negative ultrasound-guided biopsy could possibly be spared the sentinel lymph node procedure. This hypothesis is currently being studied in the SOUND and INSEMA (Intergroup Sentinel Mamma) trials, in which patients with negative axillary findings on ultrasound imaging and T1 breast cancer, suitable for breast-conserving surgery, are randomized to SLNB with or without ALND versus no further axillary staging38,43 .
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
Disclosure
The authors declare no conflict of interest. BJS
Ultrasound-guided biopsy of suspicious axillary lymph nodes
References 1 Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24 740 breast cancer cases. Cancer 1989; 63: 181–187. 2 Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH, Murphy GP. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 1980; 45: 2917–2924. 3 Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 2010; 11: 927–933. 4 Veronesi U, Viale G, Paganelli G, Zurrida S, Luini A, Galimberti V et al. Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study. Ann Surg 2010; 251: 595–600. 5 Schiffman SC, McMasters KM, Scoggins CR, Martin RC, Chagpar AB. Lymph node ratio: a proposed refinement of current axillary staging in breast cancer patients. J Am Coll Surg 2011; 213: 45–52. 6 Vinh-Hung V, Verkooijen HM, Fioretta G, Neyroud-Caspar I, Rapiti E, Vlastos G et al. Lymph node ratio as an alternative to pN staging in node-positive breast cancer. J Clin Oncol 2009; 27: 1062–1068. 7 Dings PJ, Elferink MA, Strobbe LJ, de Wilt JH. The prognostic value of lymph node ratio in node-positive breast cancer: a Dutch nationwide population-based study. Ann Surg Oncol 2013; 20: 2607–2614. 8 Giuliano AE, McCall L, Beitsch P, Whitworth PW, Blumencranz P, Leitch AM 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: 426–432. 9 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: a randomized clinical trial. JAMA 2011; 305: 569–575. 10 Francissen CM, Dings PJ, van Dalen T, Strobbe LJ, van Laarhoven HW, de Wilt JH. Axillary recurrence after a tumor-positive sentinel lymph node biopsy without axillary treatment: a review of the literature. Ann Surg Oncol 2012; 19: 4140–4149. 11 Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P 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: 297–305. 12 Harnett A, Smallwood J, Titshall V, Champion A; Guideline Development Group. Diagnosis and treatment of early breast cancer, including locally advanced disease – summary of NICE guidance. BMJ 2009; 338: b438.
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
13 Comprehensive Cancer Centre, The Netherlands. National Guideline Breast Cancer 2⋅0; 2012. http://www.oncoline.nl/ mammacarcinoom [accessed 16 January 2014]. 14 Vassallo P, Wernecke K, Roos N, Peters PE. Differentiation of benign from malignant superficial lymphadenopathy: the role of high-resolution US. Radiology 1992; 183: 215–220. 15 Houssami N, Ciatto S, Turner RM, Cody HS III, Macaskill P. Preoperative ultrasound-guided needle biopsy of axillary nodes in invasive breast cancer: meta-analysis of its accuracy and utility in staging the axilla. Ann Surg 2011; 254: 243–251. 16 van Wely BJ, de Wilt JH, Schout PJ, Kooistra B, Wauters CA, Venderinck D et al. Ultrasound-guided fine-needle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement. Breast Cancer Res Treat 2013; 140: 113–118. 17 Whiting P, Rutjes AW, Dinnes J, Reitsma J, Bossuyt PM, Kleijnen J et al. Development and validation of methods for assessing the quality of diagnostic accuracy studies. Health Technol Assess 2004; 8: iii, 1–234. 18 Bonnema J, van Geel AN, van Ooijen B, Mali SP, Tjiam SL, Henzen-Logmans SC et al. Ultrasound-guided aspiration biopsy for detection of nonpalpable axillary node metastases in breast cancer patients: new diagnostic method. World J Surg 1997; 21: 270–274. 19 Damera A, Evans AJ, Cornford EJ, Wilson AR, Burrell HC, James JJ et al. Diagnosis of axillary nodal metastases by ultrasound-guided core biopsy in primary operable breast cancer. Br J Cancer 2003; 89: 1310–1313. 20 Kuenen-Boumeester V, Menke-Pluymers M, de Kanter AY, Obdeijn IM, Urich D, Van Der Kwast TH. Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure. Eur J Cancer 2003; 39: 170–174. 21 Lemos S, Dias M, Gonçalo M, Pinto E, Fernandes G, Oliveira C et al. Detection of axillary metastases in breast cancer patients using ultrasound and colour Doppler combined with fine needle aspiration cytology. Eur J Gynaecol Oncol 2005; 26: 165–166. 22 de Kanter AY, Menke-Pluijmers MB, Henzen-Logmans SC, van Geel AN, van Eijck CJ, Wiggers T et al. Reasons for failure to identify positive sentinel nodes in breast cancer patients with significant nodal involvement. Eur J Surg Oncol 2006; 32: 498–501. 23 van Rijk MC, Deurloo EE, Nieweg OE, Gilhuijs KG, Peterse JL, Rutgers EJ et al. Ultrasonography and fine-needle aspiration cytology can spare breast cancer patients unnecessary sentinel lymph node biopsy. Ann Surg Oncol 2006; 13: 31–35. 24 Davis JT, Brill YM, Simmons S, Sachleben BC, Cibull ML, McGrath P et al. Ultrasound-guided fine-needle aspiration of clinically negative lymph nodes versus sentinel node mapping in patients at high risk for axillary metastasis. Ann Surg Oncol 2006; 13: 1545–1552. 25 Ciatto S, Brancato B, Risso G, Ambrogetti D, Bulgaresi P, Maddau C et al. Accuracy of fine needle aspiration cytology
www.bjs.co.uk
BJS
B. J. van Wely, J. H. W. de Wilt, C. Francissen, S. Teerenstra and L. J. A. Strobbe
26
27
28
29
30
31
32
33
34
(FNAC) of axillary lymph nodes as a triage test in breast cancer staging. Breast Cancer Res Treat 2007; 103: 85–91. Nori J, Vanzi E, Bazzocchi M, Bufalini FN, Distante V, Branconi F et al. Role of axillary ultrasound examination in the selection of breast cancer patients for sentinel node biopsy. Am J Surg 2007; 193: 16–20. Hinson JL, McGrath P, Moore A, Davis JT, Brill YM, Samoilova E et al. The critical role of axillary ultrasound and aspiration biopsy in the management of breast cancer patients with clinically negative axilla. Ann Surg Oncol 2008; 15: 250–255. Holwitt DM, Swatske ME, Gillanders WE, Monsees BS, Gao F, Aft RL et al. Scientific Presentation Award: The combination of axillary ultrasound and ultrasound-guided biopsy is an accurate predictor of axillary stage in clinically node-negative breast cancer patients. Am J Surg 2008; 196: 477–482. Tahir M, Osman KA, Shabbir J, Rogers C, Suarez R, Reynolds T et al. Preoperative axillary staging in breast cancer – saving time and resources. Breast J 2008; 14: 369–371. Swinson C, Ravichandran D, Nayagam M, Allen S. Ultrasound and fine needle aspiration cytology of the axilla in the pre-operative identification of axillary nodal involvement in breast cancer. Eur J Surg Oncol 2009; 35: 1152–1157. Rao R, Lilley L, Andrews V, Radford L, Ulissey M. Axillary staging by percutaneous biopsy: sensitivity of fine-needle aspiration versus core needle biopsy. Ann Surg Oncol 2009; 16: 1170–1175. Schiettecatte A, Bourgain C, Breucq C, Buls N, De Wilde V, de Mey J. Initial axillary staging of breast cancer using ultrasound-guided fine needle aspiration: a liquid-based cytology study. Cytopathology 2011; 22: 30–35. García Fernández A, Fraile M, Giménez N, Reñe A, Torras M, Canales L et al. Use of axillary ultrasound, ultrasound-fine needle aspiration biopsy and magnetic resonance imaging in the preoperative triage of breast cancer patients considered for sentinel node biopsy. Ultrasound Med Biol 2011; 37: 16–22. Solon JG, Power C, Al-Azawi D, Duke D, Hill AD. Ultrasound-guided core biopsy: an effective method of
35
36
37
38
39
40
41
42
43
detecting axillary nodal metastases. J Am Coll Surg 2012; 214: 12–17. Cools-Lartigue J, Sinclair A, Trabulsi N, Meguerditchian A, Mesurolle B, Fuhrer R et al. Preoperative axillary ultrasound and fine-needle aspiration biopsy in the diagnosis of axillary metastases in patients with breast cancer: predictors of accuracy and future implications. Ann Surg Oncol 2013; 20: 819–827. Abe H, Schacht D, Sennett CA, Newstead GM, Schmidt RA. Utility of preoperative ultrasound for predicting pN2 or higher stage axillary lymph node involvement in patients with newly diagnosed breast cancer. AJR Am J Roentgenol 2013; 200: 696–702. Neal CH, Daly CP, Nees AV, Helvie MA. Can preoperative axillary US help exclude N2 and N3 metastatic breast cancer? Radiology 2010; 257: 335–341. Gentilini O, Veronesi U. Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European Institute of Oncology of Milan (SOUND: Sentinel node vs Observation after axillary UltraSouND). Breast 2012; 21: 678–681. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, Version 3; 2012. http://www.nccn.org [accessed 8 October 2013]. Genta F, Zanon E, Camanni M, Deltetto F, Drogo M, Gallo R et al. Cost/accuracy ratio analysis in breast cancer patients undergoing ultrasound-guided fine-needle aspiration cytology, sentinel lymph node biopsy, and frozen section of node. World J Surg 2007; 31: 1155–1163. Mortellaro VE, Marshall J, Singer L, Hochwald SN, Chang M, Copeland EM et al. Magnetic resonance imaging for axillary staging in patients with breast cancer. J Magn Reson Imaging 2009; 30: 309–312. Cooper KL, Harnan S, Meng Y, Ward SE, Fitzgerald P, Papaioannou D et al. Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: a systematic review and meta-analysis. Eur J Surg Oncol 2011; 37: 187–198. Reimer T, Hartmann S, Stachs A, Gerber B. Local treatment of the axilla in early breast cancer: concepts from the National Surgical Adjuvant Breast and Bowel Project B-04 to the Planned Intergroup Sentinel Mamma Trial. Breast Care 2014; 9: 87–95.
Supporting information
Additional supporting information may be found in the online version of this article: Table S1 Literature search details (Word document)
© 2014 BJS Society Ltd Published by John Wiley & Sons Ltd
www.bjs.co.uk
BJS
