World J Surg (2012) 36:2847–2852 DOI 10.1007/s00268-012-1704-z
Correlation Between Clinical Nodal Status and Sentinel Lymph Node Biopsy False Negative Rate After Neoadjuvant Chemotherapy Maiko Takahashi • Hiromitsu Jinno • Tetsu Hayashida • Michio Sakata • Keiko Asakura Yuko Kitagawa
•
Published online: 18 July 2012 Ó Socie´te´ Internationale de Chirurgie 2012
Abstract Background Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced breast cancer. It is now being used to treat operable breast cancer to facilitate breast-conserving surgery, but the accuracy of sentinel lymph node biopsy (SLNB) in breast cancer patients receiving NAC remains open to considerable debate. Methods We enrolled 96 patients with stage II–III breast cancer who received NAC from January 2001 to July 2010. All patients underwent breast surgery and SLNB, followed immediately by complete axillary lymph node dissection (ALND). Sentinel lymph nodes were detected with blue dye and radiocolloid injected intradermally just above the tumor and then evaluated with hematoxylin and eosin and immunohistochemical staining. Results The overall identification rate for SLNB was 87.5 % (84/96); the false negative rate (FNR) was 24.5 % (12/49); and the accuracy rate was 85.7 % (72/84). The FNR was significantly lower in clinically node-negative patients than in node-positive patients before NAC (5.5 % vs. 35.5 %; p = 0.001). Accuracy was also significantly higher in clinically node-negative patients than in nodepositive patients before NAC (97.2 % vs. 77.1 %; p = 0.009). The FNR was 27.3 % among 46 clinically nodepositive patients before NAC who were clinically nodenegative after NAC. Among 12 patients with a complete M. Takahashi H. Jinno (&) T. Hayashida M. Sakata Y. Kitagawa Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8587, Japan e-mail:
[email protected] K. Asakura Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
tumor response (CR), the FNR was 0 %, compared with 26.1 % for 83 patients with a partial response and stable disease (p = 0.404). Conclusions Although associated with a high FNR after NAC, SLNB would have successfully replaced ALND in clinically node-negative patients before NAC and in patients with a CR after NAC.
Introduction Axillary lymph node status is a powerful prognostic factor for breast cancer, and the adjuvant therapy regimen is primarily dependent on the number of involved lymph nodes. Axillary lymph node dissection (ALND) is necessary for accurate staging and regional control, although it is associated with complications such as lymphedema, numbness, and pain, which occur in 6 to 30 % of patients [1, 2]. Axillary lymph node dissection is not beneficial for pathologically node-negative patients, however, so sentinel lymph node biopsy (SLNB) has been studied extensively and is considered an accurate method for assessing nodal status in such patients. If the sentinel lymph node (SLN) is negative for metastasis, then it can be assumed that the remainder of the axilla is disease free. Many studies have shown SLNB to be highly predictive with a false negative rate (FNR) of \5 % for clinically node-negative patients if performed by an experienced surgeon [3, 4]. Neoadjuvant chemotherapy (NAC) was initially introduced to downstage locally advanced breast cancer to facilitate surgery. It has resulted in both longer disease-free survival and longer overall survival, with an effect equivalent to that of adjuvant chemotherapy [5]. The indications for NAC have recently been extended to selected patients with early-stage breast cancer to allow breast-conserving
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surgery [6, 7]. Another important advantage of NAC is that it allows for an opportunity to assess sensitivity to chemotherapy in situ, thereby providing prognostic information and facilitating identification of an effective therapy [8]. Residual lymph node metastasis after NAC is a powerful prognostic factor [9], and it appears that patients who achieve CR have better disease-free survival [10]. Chemotherapy is known to induce changes at the site of the primary breast cancer that can be determined pathologically. These changes alter lymphatic drainage patterns by inducing lymphovascular shrinkage and fibrosis, as well as fatty degeneration resulting from apoptosis of the tumor cells, thereby potentially obstructing lymphatic channels with either cellular material or tumor emboli resulting in a false negative SLN [11, 12]. Previous studies on SLNB after NAC have produced conflicting results, with FNRs ranging from 0 to 33 %. Despite the increased use of both SLNB and NAC in operable breast cancer cases, there is still limited information on the effectiveness of SLNB after NAC. The purpose of the present study, therefore, was to clarify the clinical factors that correlate with the SLN identification rate and FNR by assessing the feasibility of using SLNB for patients with or without palpable adenopathy who were treated with NAC and determining its accuracy.
Patients and methods Patient selection Between January 2001 and July 2010, 96 patients with stage II–III breast cancer received NAC and underwent SLNB followed by full ALND as a component of their surgical treatment at Keio University Hospital. Pathological diagnoses were based on core needle biopsies performed on every patient prior to NAC. Fine-needle aspiration biopsy was not performed for the patients with clinically palpable lymph nodes. A total of 55 patients (57.3 %) had clinically nodepositive status before NAC. Our institutional review board approved the protocol and all patients consented in writing to their participation in this study. Evaluation of chemotherapy effects Evaluation by palpation, mammography, ultrasonography, and magnetic resonance imaging was performed before and after chemotherapy to assess the effects of chemotherapy and determine axillary lymph node status. Clinical response was assessed with the Response Evaluation Criteria in Solid Tumors guidelines. Clinical response assessment was carried out within 4 weeks before study entry and after completion of chemotherapy. Clinical
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response was determined by the response of the tumor, irrespective of axillary lymph nodes status. Neoadjuvant Chemotherapy The following chemotherapeutic regimens were administered prior to surgery: four cycles of docetaxel and capecitabine followed by four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) (35 patients); four cycles of docetaxel and 50 -deoxy-5-fluorouridine (17 patients); four cycles of FEC followed by four cycles of docetaxel (ten patients); 12 cycles of weekly docetaxel (eight patients); four cycles of docetaxel and TS-1 followed by four cycles of FEC (eight patients); four cycles of Adriamycin and cyclophosphamide (AC) followed by four cycles of docetaxel (seven patients); 12 cycles of weekly paclitaxel and trastuzumab (five patients); four cycles of FEC followed by 12 cycles of weekly paclitaxel (four patients); and four cycles of AC followed by 12 cycles of weekly paclitaxel (two patients). SLNB procedure Lymphatic mapping was performed using a combination of technetium-99m-labeled tin colloid (particle diameter: 0.2–0.4 lm) and isosulfan blue dye (US Surgical, Norwalk, CT) through November 2008. After that time, indigo-carmine (Daiichi Sankyo, Tokyo, Japan) was used as the blue dye. Tin colloid was injected intradermally just above the tumor and peritumorally the day before operation. Lymphoscintigraphy was performed 3 h after the injection of tin colloid. Sentinel lymph nodes were identified by both a handheld gamma probe (US Surgical) and the appearance of blue dye in lymphatic vessels and nodes. After induction of general anesthesia, blue dye was injected intradermally just above the tumor, and the injection site was then massaged for 5 min. All patients underwent concurrent complete ALND regardless of their individual axillary lymph node status. Pathological examination Each SLN was bisected at two levels for hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for cytokeratin. The IHC staining was performed with the anticytokeratin antibody AE1/AE3 (DAKO, Carpinteria, CA). Each non-SLN was examined on one level using H&E staining. Expression of hormone receptors and the HER2/neu protein was assessed by IHC staining (Ventana Medical Systems, Tuscon, AZ). Statistical methods The false negative rate was defined as the number of false negative cases divided by all cases that have disease.
World J Surg (2012) 36:2847–2852
Differences in categorical variables were analyzed with Fisher’s exact test; differences in mean values of continuous variables were analyzed with Student’s t test. A value of p \ 0.05 was considered statistically significant.
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Discussion In the present study, the overall identification rate and the FNR were 87.5 and 24.5 %, respectively. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial is one of the largest studies published to date on
Results Table 1 Patient and tumor characteristics
The median age at the time of diagnosis was 52 years (range: 29–78 years) and tumor size (mean ± standard deviation) determined by sonography was 3.5 ± 1.3 cm before NAC. A total of 55 patients (57.3 %) had clinically node-positive status before NAC. The percentage of clinically node-negative patients before NAC was 42.7 % (41/ 96). In terms of the clinical response to NAC, 12 patients (12.5 %) had a complete response (CR), and 70 patients (72.9 %) had a partial response (PR). Thirteen patients (13.5 %) had stable disease (SD), and one patient had progressive disease. Although ten of 12 patients with a CR were clinically node-positive before NAC, all of these ten patients were downstaged to clinically node-negative status after NAC. The downstaged rates of clinically nodal status in patients with PR and SD were 83.8 % (31/37) and 62.5 % (5/8), respectively. Axillary lymph node dissection identified pathological nodal involvement in 49 patients (51.0 %), including two CR patients (2.1 %) (Table 1). The overall identification rate was 87.5 % (84/96), and the mean number of SLN per case was 3.0 ± 2.1. Twelve of 49 patients with axillary nodal involvement had false negative SLN, yielding an FNR of 24.5 %. The negative predictive value and accuracy rate were 77.8 % (42/54) and 85.7 % (72/84), respectively (Table 2). The correlations between clinical factors and the precision of SLNB are shown in Table 3. Clinical tumor size was not significantly correlated with the identification, false negative, or accuracy rates, and clinical nodal status before NAC did not affect the identification rate. The FNR in clinically node-negative patients before NAC was significantly lower than that in node-positive patients before NAC (5.6 % vs. 35.5 %; p = 0.001). Accuracy was also significantly higher in node-negative patients than in nodepositive patients before NAC (97.2 % vs. 77.1 %; p = 0.009). The FNR among CR patients was lower, although the difference was not statistically significant in comparison to patients with other responses, including PR and SD (0 % vs. 26.1 %; p = 0.404). In addition, the identification and accuracy rates were not significantly different between CR patients and those with other responses. The FNR among 46 clinically node-positive patients before NAC who turned out to be node-negative after NAC, was 27.3 % (6/22), which was higher than for the 41 clinically nodenegative patients before and after NAC, but not significantly different (p = 0.081) (Table 4).
Number of patients (n = 96)
%
Age (years) Median
52
Range
29–78
Clinical tumor size (cm) Mean ± standard deviation
3.5 ± 1.3
Clinical nodal status Positive
55
57.3
Upper outer
50
52.1
Upper inner
12
12.5
Lower outer
11
11.5
Lower inner
9
9.4
Central
14
14.6
12 70
12.5 72.9
Stable disease
13
13.5
Progressive disease
1
1.0
Invasive ductal carcinoma
89
92.7
Invasive lobular carcinoma
4
4.2
Others
3
3.1
44
45.8
3
3.1
49
51.0
63
65.6
49
51.0
3?
22
22.9
2?
13
13.5
1?
28
29.2
0
13
13.5
Unknown
20
20.8
9
9.4
Tumor site
Clinical tumor response Complete response Partial response
Histological type
Lymphatic invasion Positive Vascular invasion Positive Axillary node involvement Positive Estrogen receptor Positive Progesterone receptor Positive HER2/neu
Pathological response Pathological complete response
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Table 2 Sentinel lymph node biopsy results n
%
Successful mapping
84/96
87.5
Mean sentinel lymph nodes identified ± standard deviation
3 ± 2.1
False negative rate
12/49
24.5
Negative predictive value
42/54
77.8
72/84
85.7
SLNB after NAC [13]. A total of 428 patients underwent SLNB with concomitant ALND after NAC, and the identification rate and the FNR were 84.8 and 10.7 %, respectively. In addition, a meta-analysis of 21 studies involving a total of 1,273 patients who received NAC followed by SLNB and ALND indicated an average identification rate of 91 % and FNR of 12 % [14]. Although our identification rate did not differ much from previously reported multicenter studies evaluating SLNB after NAC, our FNR of 24.5 % was considerably higher than that reported in other studies. The clinically node-positive rate before NAC in our study was 57.3 %, which also was considerably higher than the 30.7 % reported in the NSABP B-27 trial. One potential explanation is that the lymph nodes in clinically node-positive patients might have become sclerotic following NAC, and thus the sclerotic nodes that could still contain some residual cancer cells would block the flow of the tracer and redirect the flow to other negative nodes. Previous studies on SLNB after NAC have produced conflicting results, with FNR ranging from 0 to 33 %. This conflicting range of FNR was due in part to the lack of uniform definition of FNR. In some published reports, FNR was calculated as false negative cases divided by false negative plus true negative cases, although the definition of FNR was false negative cases divided by false negative plus true positive cases.
According to our study results, there was a significant difference between clinically node-positive and clinically node-negative patients before NAC in terms of their FNR. The increasing use of NAC has created considerable debate with respect to the timing of SLNB, which may affect decisions relating to systemic treatment and use of radiation therapy. Neoadjuvant chemotherapy has been shown to downstage nodal status in a relatively large proportion of patients (23–40 %) [7, 13, 15], and this is an important advantage for performing nodal staging after NAC compared with nodal staging before NAC. Other advantages of SLNB after NAC would be avoiding any unnecessary delay in administering NAC, and patients with a pathologically nodenegative SLN after NAC would require only one surgical procedure instead of two. In contrast, however, the advantages of performing SLNB before NAC are obtaining an accurate assessment of initial axillary lymph node involvement as well as a clearly established FNR. The main clinical factor influencing the FNR in our study was clinical nodal status before NAC. The FNR among clinically node-negative patients before NAC was significantly lower than that among node-positive patients (5.5 % vs. 35.5 %; p \ 0.05). The FNR among the clinically node-negative patients in our study is similar to the range reported in a meta-analyses of SLNB without NAC (5.1–9 %) [16–18] Le Bouedec and colleagues [19] reported no false negative cases in 29 clinically nodenegative patients before NAC compared to a FNR of 30 % in 27 clinically node-positive patients before NAC. Tausch et al. [20] also reported a trend toward a higher FNR in initial clinically node-positive patients. On the other hand, the NSABP B-27 trial [13] reported no effect of clinical nodal status on the FNR. The accuracy of SLNB in clinically node-positive patients, who turned out to be node-negative after NAC, remains in question. The FNR of 46 clinically node-
Table 3 Sentinel lymph node biopsy results based on clinical factors Identification rate
False negative rate
n (%)
p Value
\3 cm
24/28 (85.7)
0.715
C3 cm
60/68 (88.2)
n (%)
Accuracy p Value
n (%)
p Value
0.339
19/24 (79.2)
0.127
Tumor size before NAC 5/15 (33.3) 7/34 (20.6)
53/60 (88.3)
Clinical nodal status before NAC Node negative
36/41 (87.8)
Node positive
48/55 (87.3)
0.961
1/18 (5.6)
0.001
11/31 (35.5)
35/36 (97.2)
0.009
37/48 (77.1)
Clinical response Complete response Partial response ? stable disease NAC Neoadjuvant chemotherapy
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11/12 (91.7) 72/83 (86.7)
0.392
0/2 (0) 12/46 (26.1)
0.404
11/11 (100) 60/72 (83.3)
0.143
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Table 4 False negative rate and clinical nodal status after NAC correlation Clinical nodal status before NAC
Clinical nodal status after NAC
Identification rate
Node negative
Node negative
36/41 (87.8)
1/18 (5.6)
35/36 (97.2)
Node positive
Node negative
40/46 (87.0)
6/22 (27.3)
34/40 (85.0)
Node positive
Node positive
8/9 (88.9)
5/9 (55.6)
3/8 (37.5)
False negative rate
Accuracy (%)
positive patients who were node-negative after NAC was a disappointing 27.3 % (6/22) in our study. A recently published small retrospective analysis of SLNB after NAC reported a high FNR of 25 % among patients who had cytologically documented positive nodes before NAC [21]. Lee et al. [22] compared the identification rate and FNR of SLNB in 875 clinically node-positive patients with and without NAC The identification rate in patients receiving NAC was 77.6 %, which was significantly lower than for those who did not receive NAC (97.0 %; p \ 0.001), but the FNR in those patients receiving NAC (5.6 %) was similar to that observed among patients who did not receive NAC (7.4 %). In the present study, the FNR in patients achieving a CR was 0 %, a figure lower than that for patients with other types of responses. One possible explanation is the marked difference in the pathological node-positive rate between CR patients and patients with other responses (16.7 % vs. 55.4 %; p = 0.01). Kinoshita et al. [23] reported no statistically significant difference in the FNR between patients with CR and other types of response after NAC. In conclusion, the results of our study indicate that although SLNB after NAC is associated with a high FNR primarily because of clinically node-positive patients who were determined to be clinically node-negative after NAC, SLNB can nevertheless successfully replace ALND for patients who are either clinically node-negative before NAC or have achieved a CR after NAC. Clinically nodepositive patients who are subsequently found to be clinically node-negative after NAC, should continue to undergo a definitive ALND. Acknowledgments This work was supported by a Japanese Ministry of Education, Culture, Sports, Science and Technology Grantin-Aid for Scientific Research [C] (#21591677 MT). Conflict of interest The authors have no relevant conflict of interests.
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