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Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients
Clinical Radiology 70 (2015) 716e722
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Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients S.J. Hyun, E.-K. Kim, J.H. Yoon, H.J. Moon, M.J. Kim* Department of Radiology, Breast Cancer Clinic, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea
article in formation Article history: Received 2 September 2014 Received in revised form 27 February 2015 Accepted 19 March 2015
AIM: To evaluate whether adding magnetic resonance imaging (MRI) to ultrasound (US) and US-guided fine-needle aspiration (US-FNA) can reduce the false-negative rate (FNR) in the diagnosis of axillary lymph node metastasis (ALNM) in breast cancer patients, and to assess false-negative diagnosis of N2 and N3 disease when adding MRI to US and US-FNA. MATERIALS AND METHODS: From March 2012 to February 2013, 497 breast cancer patients were included in the study. ALNM was evaluated according to US and US-FNA prior to MRI. Second-look US was performed when MRI showed positive findings of ALNM. If second-look US also revealed a positive finding, US-FNA was performed. Diagnostic performance, including FNR, was calculated for US and US-FNA with and without MRI. The negative predictive value (NPV) of N2 and N3 disease was evaluated in negative cases based on US and US-FNA with MRI. RESULTS: A total of 159 of 497 (32.0%) patients were found to have ALNM. Among them, 92 patients were diagnosed with metastasis on US and US-FNA. When adding MRI to US and USFNA, an additional six patients were diagnosed with metastasis. The FNR of diagnosis of ALNM was improved by the addition of MRI (42.1% versus 38.4%, p ¼ 0.0143). The NPV for N2 and N3 disease was 98% (391/399) based on US and US-FNA with MRI. CONCLUSION: Adding MRI to US and US-FNA could reduce the FNR of the diagnosis of ALNM. Furthermore, US and US-FNA with MRI may exclude 98% of N2 and N3 disease. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction In patients with breast cancer, the evaluation of axillary lymph node (ALN) status is important in determining * Guarantor and correspondent: M.J. Kim, Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: þ82 2 2228 7400; fax: þ82 2 393 3035. E-mail address: [email protected] (M.J. Kim).
optimal treatment and predicting prognosis.1,2 Traditionally, this has been assessed by sentinel lymph node biopsy (SLNB). After a positive SLNB, subsequent ALN dissection (ALND) was typically pursued. Ultrasound (US)-guided fineneedle aspiration (US-FNA) has been widely accepted for preoperative axillary staging, as it is less invasive than SLNB and involves no radiation hazard.3 Furthermore, with preoperative detection of ALNM by US-FNA, patients may have the opportunity to undergo neoadjuvant chemotherapy (NAC).
http://dx.doi.org/10.1016/j.crad.2015.03.004 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
S.J. Hyun et al. / Clinical Radiology 70 (2015) 716e722
However, a recent meta-analysis revealed the relatively low sensitivity and high false-negative rate (FNR; 50% and 25%, respectively) of US and US-FNA, which may be a limitation of these modalities in the evaluation of ALN status.4 Breast magnetic resonance imaging (MRI) is now widely used to evaluate accurate tumour extent. Breast MRI that includes the axillary region may provide radiologists with the chance to re-evaluate ALNs. Therefore, breast MRI is expected to play a role in reducing the FNR of ALN metastasis (ALNM) diagnosis. Although Fernandez et al.5 reported that there is no added benefit of adding MRI to US and USFNA in detection of ALNM compared to US and US-FNA alone, their study had a small patient population. Therefore, the aim of the present study was to evaluate whether the FNR of diagnosis of ALNM in breast cancer patients could be reduced by adding MRI to US and US-FNA. Furthermore, a second aim was to assess the amount of patients with false-negative N2 and N3 disease when adding MRI to US and US-FNA.
Materials and methods Study population The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Signed informed consent was obtained from all patients prior to US-FNA. Between March 2012 and February 2013, 668 patients diagnosed with breast cancer with available mammography and US underwent breast MRI. Among them, 171 patients were excluded because they did undergo surgery because NAC was planned (n ¼ 57), did undergo surgery at Severance Hospital (n ¼ 31), or had final diagnoses other than invasive breast cancer (n ¼ 83; ductal carcinoma in situ (DCIS), n ¼ 81; dermatofibrosarcoma, n ¼ 1; spindle cell sarcoma, n ¼ 1). Consequently, a total of 497 patients who were diagnosed with invasive breast cancer, underwent preoperative breast MRI, and underwent surgery at Severance Hospital were included in the study.
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performed using a 23 G needle attached to a 2 ml syringe using freehand technique. Acquired cells were deposited on glass slides and stained according to the standard Papanicolaou stain method. The slides were evaluated by one of nine experienced cytopathologists. Cytological results were classified as negative or positive for metastasis.
MRI evaluation MRI was performed using a 3 T MRI system (Discovery 750, GE Medical Systems, Milwaukee, WI, USA). All patients were imaged in the prone position using an eight-channel dedicated breast surface coil. Imaging was performed prior to a rapid bolus injection and six times after injection of contrast medium. The bolus injection consisted of 0.1 ml/ kg gadobutrol (Gadovist, Bayer, Berlin, Germany) and a 20 ml saline flush delivered through an intravenous cannula inserted in an antecubital vein. The imaging protocol included axial fast spin-echo T2weighted images, and post-contrast-enhanced axial and sagittal T1-weighted images with fat saturation by using VIBRANT-FLEX technique of GE Medical Systems, with a 32 cm field of view, a 3 mm section thickness without a gap, a repetition time of 6.2 milliseconds, an echo time of 1.3 milliseconds, a flip angle of 10 , matrix of 280 512, and a resulting total scan time of 8 minutes. Contrast-enhanced axial T1-weighted images were evaluated in a second scanning phase, which was obtained 76 seconds after the contrast medium injection, which showed peak enhancement. Images in the sagittal orientation were obtained in delayed phase after dynamic contrast-enhanced axial images were obtained. One radiologist (M.J.K.) with 10 years of experience in breast imaging evaluated the results of preoperative MRI. ALN was considered positive when one or more suspicious MRI findings were noted. Criteria to determine positive nodes included a short-axis diameter exceeding 10 mm, round shape (ratio of longest to shortest axes smaller than 1.5), eccentric cortical thickening, and loss of fatty hilum.9e12 Using these criteria, ALNs were classified as either negative or positive.
US evaluation
Second-look US and US-FNA
Preoperative ALN status was evaluated using US and USFNA during bilateral whole-breast US examinations performed prior to MRI. US and US-FNA were performed using a high-frequency linear array transducer (12 MHz) on a Phillips IU 22 (Philips Medical Systems, Bothell, WA, USA) or GE LOGIQ E9 (GE Medical Systems, Milwaukee, WI, USA) by nine breast radiologists with 1e15 years of experience. Positive US findings of ALNM were loss of fat hilum, cortical thickening of more than 3 mm, irregular or round shape, or increased non-hilar peripheral blood flow.6e8 If the ALN exhibited one or more of the positive US features described above, US-FNA was performed.
Second-look US in the axillary area was performed if an ALN was considered positive based on MRI. If second-look US also suspicious ALN based on US criteria, US-FNA was performed. If second-look US demonstrated no suspicious ALN findings, patients underwent SLNB, and the results were reviewed.
US-FNA of ALN US-FNA was performed when suspicious findings of ALN were detected on US. Under US guidance, FNA was
Data analysis We retrospectively reviewed the radiologic and clinicopathological findings of all patients included in this study. For analytic purposes, metastasis and atypical cytological results were regarded as cytological positive results on FNA, while negative for malignancy and inadequate sampling were considered negative results, because an ALN with inadequate sampling would undergo SLNB as an ALN with negative cytology.13
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Preoperative reports of ALN status based on US and USFNA with MRI were correlated with final histopathological reports. Final histopathology of an ALN was determined either by cytology results before NAC or by surgical procedures such as SLNB or ALND. N-staging of breast cancer was based on the American Joint Committee on Cancer recommendations, 7th edition.14 Positive ALNs were defined by either positive results on surgical histopathology or USFNA cytology prior to NAC. If there was no evidence of positive surgical histopathology or US-FNA cytology, the final histopathology was considered negative for malignancy. Using these selection criteria, true-positive (TP), truenegative (TN), false-positive (FP), and false-negative (FN) rates of axillary US and US-FNA with MRI were calculated. The results of US and US-FNA with MRI for diagnosis of ALNM were evaluated with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), FNR, and accuracy as follows: sensitivity, TP/ (TP þ FN); specificity, TN/(TN þ FP); PPV, TP/(TP þ FP); NPV, TN/(TN þ FN); FNR, FN/(TP þ FN); and accuracy, (TP þ TN)/ (TP þ FN þ FP þ TN). To compare the differences in diagnostic performance between US and US-FNA with or without MRI, weighted least squares analysis was used. In addition, the results of US and US-FNA with MRI for diagnosis of advanced N2 and N3 disease were evaluated with respect to NPV as follows: 1(N2 and N3)/(FN þ TN). Values of p < 0.05 were considered to be statistically significant. Statistical analysis was performed using commercially available statistical software (SAS version 9.2; SAS Institute, Cary, NC, USA).
Results The mean age of the 497 women was 52 years (range 21e86 years). A total of 159 of 497 (32%) patients were
found to have positive ALNs on final histopathological examination. The remaining 338 patients were found to have negative ALNs. The flowchart for included patients and staging procedures in evaluation of ALN is shown in Fig 1.
Diagnostic performance of US and US-FNA One hundred and fifty-nine patients had ALNs with positive US findings and 338 patients had ALNs with negative US findings on axillary US. Among the 159 patients who had ALNs with positive US findings, 92 patients were positive for malignancy on US-FNA, whereas 67 patients were negative. The sensitivity, specificity, PPV, NPV, FNR, and accuracy of US-FNA were 57.9% (92/159), 100% (338/ 338), 100% (92/92), 83.5% (338/405), 42.1% (67/159), and 86.5% (430/497), respectively.
Diagnostic performance of US and US-FNA with MRI After review of preoperative breast MRI, second-look US of the axillary area was performed in patients with positive MRI findings previously undetected on US images. Among the 338 patients with negative findings on initial US, 21 patients had positive findings on breast MRI and underwent second-look US. Among these 21 patients, 17 were found to have positive US findings on second-look US. US-FNA was performed in these 17 patients, and six patients were reported to have ALNM. In total, six patients were diagnosed with ALNM due to added breast MRI. All of these six ALNM were located in upper portion of the axilla, and the mean size of ALNM was 12 mm (range 8e17 mm), bigger than contralateral ALN The size of contralateral ALNs were <10 mm, below the positive MRI criteria. Five out of six ALNM were located at Level 1 of the axilla, at the depth of the pectoralis minor muscle, and one was located at Level 2, posterior to the pectoralis minor muscle.
Figure 1 Flowchart for patients undergoing staging procedures in the evaluation of ALNs.
S.J. Hyun et al. / Clinical Radiology 70 (2015) 716e722 Table 1 Diagnostic performance of ultrasound (US) and US-fine-needle aspiration (FNA) with or without added magnetic resonance imaging (MRI) for the diagnosis of axillary lymph node metastasis. Diagnostic performance
US and US-FNA
US and US-FNA with MRI
p-Value
Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) FNR (%)
57.9 100.0 100.0 83.5 86.5 42.1
61.6 100.0 100.0 84.7 87.7 38.4
0.0143 >0.9999 >0.9999 0.0143 0.0143 0.0143
(50.2e65.5) (100.0e100.0) (100.0e100.0) (79.8e87.1) (83.5e89.5) (34.5e49.8)
(54.1e69.2) (100.0e100.0) (100.0e100.0) (81.2e88.2) (84.8e90.6) (30.8e45.9)
Numbers in parentheses are 95% confidence intervals. PPV, positive predictive value; NPV, negative predictive value; FNR, falsenegative rate.
The sensitivity, specificity, PPV, NPV, FNR, and accuracy of US and US-FNA with MRI were 61.6% (98/159), 100% (338/ 338), 100% (98/98), 84.7% (338/399), 38.4% (61/159), and 87.7% (436/497), respectively. By adding breast MRI, the sensitivity and NPV increased, whereas FNR decreased (42.1% to 38.4%, p ¼ 0.0143; Table 1, Fig 2).
False-negative nodal disease detected through US and US-FNA with MRI Of the 497 patients included in the study, 399 patients were negative for ALNM on US and US-FNA with MRI. Among these, 61 patients were confirmed to have falsenegative nodal disease with US and US-FNA with MRI. Among 61 patients, six (1.5%) were classified as having Stage N2 disease (range 4e6, median 5.5, maximum size 8 mm), and two (0.5%) were classified as having Stage N3 disease (range 10e18, median 14, maximum size 12 mm; Fig 3). All of these false-negative N2 and N3 disease cases were located at Level 1 of the axilla. Seven out of eight cases of false-negative ALNM were 3e8 mm in size, below the positive MRI criteria in the present study. Only one was >10 mm, but it was classified as clinically N0 because of negative cytology results. The NPV of US and US-FNA with added MRI for excluding N2 and N3 disease was 98% (391 of
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399). The characteristics of false-negative N2 and N3 disease are shown in Table 2.
Discussion In breast cancer patients, preoperative detection of ALNM is important because it determines the treatment and surgery options available to patients.1,2 Currently, US and US-FNA are widely accepted as preoperative diagnostic tools for evaluation of ALNM because of their low morbidity, cost effectiveness, and high diagnostic performance.4,5,7,15 However, these studies also have a variable range of FNR (5e79%) according to the characteristics of the population enrolled, interobserver variability for the detection of potentially metastatic ALNs, and the expertise of the technician performing US-FNA. In cases of false-negative ALNM diagnosed through US and US-FNA, patients might undergo unnecessary SLNB for evaluation of ALN status. Furthermore, patients might be deprived of the opportunity to select other treatment options, such as NAC, prior to surgery. The FNR has been reported to depend on various clinicopathological factors, such as palpability and US findings of ALN, the grade of the primary breast tumour, the number of underlying metastatic ALNs, and the types of primary breast cancer included.15e24 The FNR of US-FNA only accounted for 5e10% of clinically palpable ALNs15 compared to the 37e79% of clinically negative (non-palpable and having at least one suspicious US feature) false-negative ALNs.15,17,19,20,23,24 In the present study, the FNR of US and US-FNA (42.1%, 67 of 159) was within the lowest range of values reported for FNR in clinically negative ALNs. Moreover, the FNR was further improved to 38.4% by the addition of breast MRI (42.1% versus 38.4%, p ¼ 0.0143). The criteria for diagnosing ALNM using breast MRI includes the morphology, number, and size of LNs, and kinetic information using dynamic study. However, these criteria are not yet well established. Accordingly, the predictability for ALNM using MRI is still under debate.5 In the present study, the morphology and size criteria were applied. With
Figure 2 A 48-year-old woman with a palpable mass in the right breast. Initial US identified a suspicious palpable mass but showed no pathological ALNs in the ipsilateral axilla. The mass was confirmed to be invasive ductal carcinoma (IDC) by US-guided biopsy. (a) At MRI, the contrast-enhanced T1-weighted fat-suppression images showed a 2 cm mass in the right upper outer breast, confirmed to be IDC. (b) A round ALN (arrow), suggesting possible metastasis, was seen at Level 1 of the right axilla. (c) Second-look US was performed on the right axillary region and a corresponding suspicious round ALN was noted. US-FNA confirmed the lesion to be a metastatic ALN, and ALND confirmed the diagnosis.
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Figure 3 A 40-year-old woman with a palpable mass in her right breast. The mass was confirmed to be IDC with US-guided biopsy. (a) Initial US revealed a thin, concentric cortex and prominent fatty hilum in the ipsilateral axilla (arrows). (b) At MRI, contrast-enhanced T1-weighted fatsuppression imaging showed an irregularly shaped mass in the right upper breast, which was confirmed to be IDC. (c) Contrast-enhanced T1weighted sagittal image showed only benign-looking ALNs in the right axilla (arrows). (d) Contrast-enhanced T1-weighted coronal imaging showed no pathologically enlarged ALNs in the right axilla (circle). There were no suspicious features suggesting metastasis. However, final histopathology revealed metastatic carcinoma in 10 out of 10 ALNs, with the largest measuring 7 mm, suggesting advanced N3 disease.
Table 2 False-negative N2 and N3 disease detected using ultrasound (US) and US-fine-needle aspiration (FNA) with added magnetic resonance imaging (MRI). Case no.
Age (years)
T-staging
N-staging (number of ALNM)
Maximum size of ALNM (mm)
Histological type
1 2 3 4 5 6 7 8*
46 42 63 45 56 25 40 54
T2 T2 T2 T1c T2 T1c T2 T1c
N2 N2 N2 N2 N2 N2 N3 N3
3 5 6 7 8 4 8 12
Mixed invasive lobular and ductal carcinoma IDC IDC IDC IDC IDC IDC Invasive apocrine carcinoma
(6) (6) (4) (7) (6) (5) (10) (18)
ALNM, axillary lymph node metastasis; IDC, invasive ductal carcinoma. * False negative case that showed positive findings on US and MRI, but classified as clinically N0 because of negative cytology result.
the morphological criteria used in the present study, Fernandez et al.5 suggested that axillary MRI did not improve the preoperative work-up, as it had only 36% sensitivity for detecting ALNM in breast cancer patients. Although the generalization of the present study was limited by application of breast MRI to only one-fifth of the study population and the ambiguity of their indications for breast MRI, 36% was a much lower sensitivity than expected. When kinetic analysis of lymph node enhancement and specially designed breast coils to cover the axillary area were included, the sensitivity and specificity of axillary MRI were greatly improved to 83% and 90% in the study of Kvistad et al.25 However, their study still involved falsepositive detection of benign LNs with abnormal increases in signal intensity (SI). Benign lymph node disease, such as lymphoid hyperplasia, has been reported to show rapid enhancement on MRI in other studies.26
Mortellaro et al.10 suggested that criteria including the number of ALNs and the loss of fatty hilum were more useful than kinetic analysis of ALNs for the diagnosis of metastasis.10 They suggested that breast MRI may provide radiologists the chance to confirm ALN status without additional invasive procedures. This extra step can prevent unnecessary SLNB in cases with positive results, which was consistent with the present results. Their criteria were not analysed for false-positive interpretation of MRI, which was then proven negative through second-look US (n ¼ 3) and second-look US with FNA (n ¼ 10, Fig 1). However, in the present study, information regarding previous axillary US and US-FNA was provided during the interpretation of axillary MRI, which prevented the study of sensitivity and specificity of breast MRI alone. Although the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial suggested that intensive
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therapy, such as complete axillary dissection, may not be beneficial in cases of minimally invasive N1 disease,27 results were limited in cases with breast-conserving surgery. The understanding of whether N2 or N3 can be excluded using breast US or another imaging method is important for the determination of surgical extent. Based on this suggestion, Neal et al.28 reported that preoperative US can exclude 96% of N2 or N3 disease. However, their study was based only on US, which is non-invasive, but well-known for high interobserver variability, limiting its generalizability in practice at this time. In the present study, US and US-FNA were used, the most widely accepted techniques for preoperative axillary staging. Although more invasive than US alone, this combination can confirm cytological metastasis with objective proof and show excellent PPV up to 100%, much higher than that of US alone (66.7%, 106 of 159 in Fig 1). This may obviate the need for SLNB in cases with cytologically proven metastasis. In the present study, breast MRI was performed without any additional burden on the patient because all patients with breast cancer underwent breast MRI for the evaluation of disease extent during the study period. Although it could not be demonstrated how many cases of N2 or N3 disease were excluded by MRI, axillary evaluation using breast MRI may be a useful adjunct because MRI is an objective method of counting nodes and is easy to generalize. The present findings suggest that axillary US and US-FNA with MRI can almost entirely exclude advanced N2 and N3 disease in invasive breast cancer patients with a NPV of 98%. With only six extra ALNM identified by added MRI, breast MRI may not be considered to be cost effective if it were performed only for axillary evaluation; however, added MRI is valuable for the detection of abnormal ALN as appropriate treatment plans can be formulated when breast MRI is performed for preoperative evaluation. The present study has several limitations. First, nine different radiologists with varying degrees of experience performed axillary US and US-FNA, and therefore, interobserver variability may have affected the results. Second, MRI was performed as the last diagnostic examination; therefore, these results may have been influenced by previous US and US-FNA results. Third, in the authors’ institution, most patients who were confirmed to have ALNM underwent NAC. In these cases, surgery was performed after NAC. Therefore, the number of patients who initially had N2 or N3 disease could not be evaluated, because after NAC, proven metastatic ALNs were converted to negative. In the same manner, additional detection of N2 or N3 disease by the addition of MRI could not be evaluated. Fourth, all breast MRI examinations were reported by one radiologist with 10 years of experience, so generalization of the results is limited and further evaluation is needed. In conclusion, breast MRI in combination with US and US-FNA increases sensitivity and decreases FNR while retaining high specificity, because it provides an opportunity to re-evaluate ALNs. This additional imaging technique will help determine the optimal treatment approach in breast cancer patients.
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Adding MRI to ultrasound and ultrasound-guided fine-needle aspiration reduces the false-negative rate of axillary lymph node metastasis diagnosis in breast cancer patients S.J. Hyun, E.-K. Kim, J.H. Yoon, H.J. Moon, M.J. Kim* Department of Radiology, Breast Cancer Clinic, Severance Hospital, Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Republic of Korea
article in formation Article history: Received 2 September 2014 Received in revised form 27 February 2015 Accepted 19 March 2015
AIM: To evaluate whether adding magnetic resonance imaging (MRI) to ultrasound (US) and US-guided fine-needle aspiration (US-FNA) can reduce the false-negative rate (FNR) in the diagnosis of axillary lymph node metastasis (ALNM) in breast cancer patients, and to assess false-negative diagnosis of N2 and N3 disease when adding MRI to US and US-FNA. MATERIALS AND METHODS: From March 2012 to February 2013, 497 breast cancer patients were included in the study. ALNM was evaluated according to US and US-FNA prior to MRI. Second-look US was performed when MRI showed positive findings of ALNM. If second-look US also revealed a positive finding, US-FNA was performed. Diagnostic performance, including FNR, was calculated for US and US-FNA with and without MRI. The negative predictive value (NPV) of N2 and N3 disease was evaluated in negative cases based on US and US-FNA with MRI. RESULTS: A total of 159 of 497 (32.0%) patients were found to have ALNM. Among them, 92 patients were diagnosed with metastasis on US and US-FNA. When adding MRI to US and USFNA, an additional six patients were diagnosed with metastasis. The FNR of diagnosis of ALNM was improved by the addition of MRI (42.1% versus 38.4%, p ¼ 0.0143). The NPV for N2 and N3 disease was 98% (391/399) based on US and US-FNA with MRI. CONCLUSION: Adding MRI to US and US-FNA could reduce the FNR of the diagnosis of ALNM. Furthermore, US and US-FNA with MRI may exclude 98% of N2 and N3 disease. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction In patients with breast cancer, the evaluation of axillary lymph node (ALN) status is important in determining * Guarantor and correspondent: M.J. Kim, Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea. Tel.: þ82 2 2228 7400; fax: þ82 2 393 3035. E-mail address: [email protected] (M.J. Kim).
optimal treatment and predicting prognosis.1,2 Traditionally, this has been assessed by sentinel lymph node biopsy (SLNB). After a positive SLNB, subsequent ALN dissection (ALND) was typically pursued. Ultrasound (US)-guided fineneedle aspiration (US-FNA) has been widely accepted for preoperative axillary staging, as it is less invasive than SLNB and involves no radiation hazard.3 Furthermore, with preoperative detection of ALNM by US-FNA, patients may have the opportunity to undergo neoadjuvant chemotherapy (NAC).
http://dx.doi.org/10.1016/j.crad.2015.03.004 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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However, a recent meta-analysis revealed the relatively low sensitivity and high false-negative rate (FNR; 50% and 25%, respectively) of US and US-FNA, which may be a limitation of these modalities in the evaluation of ALN status.4 Breast magnetic resonance imaging (MRI) is now widely used to evaluate accurate tumour extent. Breast MRI that includes the axillary region may provide radiologists with the chance to re-evaluate ALNs. Therefore, breast MRI is expected to play a role in reducing the FNR of ALN metastasis (ALNM) diagnosis. Although Fernandez et al.5 reported that there is no added benefit of adding MRI to US and USFNA in detection of ALNM compared to US and US-FNA alone, their study had a small patient population. Therefore, the aim of the present study was to evaluate whether the FNR of diagnosis of ALNM in breast cancer patients could be reduced by adding MRI to US and US-FNA. Furthermore, a second aim was to assess the amount of patients with false-negative N2 and N3 disease when adding MRI to US and US-FNA.
Materials and methods Study population The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Signed informed consent was obtained from all patients prior to US-FNA. Between March 2012 and February 2013, 668 patients diagnosed with breast cancer with available mammography and US underwent breast MRI. Among them, 171 patients were excluded because they did undergo surgery because NAC was planned (n ¼ 57), did undergo surgery at Severance Hospital (n ¼ 31), or had final diagnoses other than invasive breast cancer (n ¼ 83; ductal carcinoma in situ (DCIS), n ¼ 81; dermatofibrosarcoma, n ¼ 1; spindle cell sarcoma, n ¼ 1). Consequently, a total of 497 patients who were diagnosed with invasive breast cancer, underwent preoperative breast MRI, and underwent surgery at Severance Hospital were included in the study.
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performed using a 23 G needle attached to a 2 ml syringe using freehand technique. Acquired cells were deposited on glass slides and stained according to the standard Papanicolaou stain method. The slides were evaluated by one of nine experienced cytopathologists. Cytological results were classified as negative or positive for metastasis.
MRI evaluation MRI was performed using a 3 T MRI system (Discovery 750, GE Medical Systems, Milwaukee, WI, USA). All patients were imaged in the prone position using an eight-channel dedicated breast surface coil. Imaging was performed prior to a rapid bolus injection and six times after injection of contrast medium. The bolus injection consisted of 0.1 ml/ kg gadobutrol (Gadovist, Bayer, Berlin, Germany) and a 20 ml saline flush delivered through an intravenous cannula inserted in an antecubital vein. The imaging protocol included axial fast spin-echo T2weighted images, and post-contrast-enhanced axial and sagittal T1-weighted images with fat saturation by using VIBRANT-FLEX technique of GE Medical Systems, with a 32 cm field of view, a 3 mm section thickness without a gap, a repetition time of 6.2 milliseconds, an echo time of 1.3 milliseconds, a flip angle of 10 , matrix of 280 512, and a resulting total scan time of 8 minutes. Contrast-enhanced axial T1-weighted images were evaluated in a second scanning phase, which was obtained 76 seconds after the contrast medium injection, which showed peak enhancement. Images in the sagittal orientation were obtained in delayed phase after dynamic contrast-enhanced axial images were obtained. One radiologist (M.J.K.) with 10 years of experience in breast imaging evaluated the results of preoperative MRI. ALN was considered positive when one or more suspicious MRI findings were noted. Criteria to determine positive nodes included a short-axis diameter exceeding 10 mm, round shape (ratio of longest to shortest axes smaller than 1.5), eccentric cortical thickening, and loss of fatty hilum.9e12 Using these criteria, ALNs were classified as either negative or positive.
US evaluation
Second-look US and US-FNA
Preoperative ALN status was evaluated using US and USFNA during bilateral whole-breast US examinations performed prior to MRI. US and US-FNA were performed using a high-frequency linear array transducer (12 MHz) on a Phillips IU 22 (Philips Medical Systems, Bothell, WA, USA) or GE LOGIQ E9 (GE Medical Systems, Milwaukee, WI, USA) by nine breast radiologists with 1e15 years of experience. Positive US findings of ALNM were loss of fat hilum, cortical thickening of more than 3 mm, irregular or round shape, or increased non-hilar peripheral blood flow.6e8 If the ALN exhibited one or more of the positive US features described above, US-FNA was performed.
Second-look US in the axillary area was performed if an ALN was considered positive based on MRI. If second-look US also suspicious ALN based on US criteria, US-FNA was performed. If second-look US demonstrated no suspicious ALN findings, patients underwent SLNB, and the results were reviewed.
US-FNA of ALN US-FNA was performed when suspicious findings of ALN were detected on US. Under US guidance, FNA was
Data analysis We retrospectively reviewed the radiologic and clinicopathological findings of all patients included in this study. For analytic purposes, metastasis and atypical cytological results were regarded as cytological positive results on FNA, while negative for malignancy and inadequate sampling were considered negative results, because an ALN with inadequate sampling would undergo SLNB as an ALN with negative cytology.13
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Preoperative reports of ALN status based on US and USFNA with MRI were correlated with final histopathological reports. Final histopathology of an ALN was determined either by cytology results before NAC or by surgical procedures such as SLNB or ALND. N-staging of breast cancer was based on the American Joint Committee on Cancer recommendations, 7th edition.14 Positive ALNs were defined by either positive results on surgical histopathology or USFNA cytology prior to NAC. If there was no evidence of positive surgical histopathology or US-FNA cytology, the final histopathology was considered negative for malignancy. Using these selection criteria, true-positive (TP), truenegative (TN), false-positive (FP), and false-negative (FN) rates of axillary US and US-FNA with MRI were calculated. The results of US and US-FNA with MRI for diagnosis of ALNM were evaluated with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), FNR, and accuracy as follows: sensitivity, TP/ (TP þ FN); specificity, TN/(TN þ FP); PPV, TP/(TP þ FP); NPV, TN/(TN þ FN); FNR, FN/(TP þ FN); and accuracy, (TP þ TN)/ (TP þ FN þ FP þ TN). To compare the differences in diagnostic performance between US and US-FNA with or without MRI, weighted least squares analysis was used. In addition, the results of US and US-FNA with MRI for diagnosis of advanced N2 and N3 disease were evaluated with respect to NPV as follows: 1(N2 and N3)/(FN þ TN). Values of p < 0.05 were considered to be statistically significant. Statistical analysis was performed using commercially available statistical software (SAS version 9.2; SAS Institute, Cary, NC, USA).
Results The mean age of the 497 women was 52 years (range 21e86 years). A total of 159 of 497 (32%) patients were
found to have positive ALNs on final histopathological examination. The remaining 338 patients were found to have negative ALNs. The flowchart for included patients and staging procedures in evaluation of ALN is shown in Fig 1.
Diagnostic performance of US and US-FNA One hundred and fifty-nine patients had ALNs with positive US findings and 338 patients had ALNs with negative US findings on axillary US. Among the 159 patients who had ALNs with positive US findings, 92 patients were positive for malignancy on US-FNA, whereas 67 patients were negative. The sensitivity, specificity, PPV, NPV, FNR, and accuracy of US-FNA were 57.9% (92/159), 100% (338/ 338), 100% (92/92), 83.5% (338/405), 42.1% (67/159), and 86.5% (430/497), respectively.
Diagnostic performance of US and US-FNA with MRI After review of preoperative breast MRI, second-look US of the axillary area was performed in patients with positive MRI findings previously undetected on US images. Among the 338 patients with negative findings on initial US, 21 patients had positive findings on breast MRI and underwent second-look US. Among these 21 patients, 17 were found to have positive US findings on second-look US. US-FNA was performed in these 17 patients, and six patients were reported to have ALNM. In total, six patients were diagnosed with ALNM due to added breast MRI. All of these six ALNM were located in upper portion of the axilla, and the mean size of ALNM was 12 mm (range 8e17 mm), bigger than contralateral ALN The size of contralateral ALNs were <10 mm, below the positive MRI criteria. Five out of six ALNM were located at Level 1 of the axilla, at the depth of the pectoralis minor muscle, and one was located at Level 2, posterior to the pectoralis minor muscle.
Figure 1 Flowchart for patients undergoing staging procedures in the evaluation of ALNs.
S.J. Hyun et al. / Clinical Radiology 70 (2015) 716e722 Table 1 Diagnostic performance of ultrasound (US) and US-fine-needle aspiration (FNA) with or without added magnetic resonance imaging (MRI) for the diagnosis of axillary lymph node metastasis. Diagnostic performance
US and US-FNA
US and US-FNA with MRI
p-Value
Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) FNR (%)
57.9 100.0 100.0 83.5 86.5 42.1
61.6 100.0 100.0 84.7 87.7 38.4
0.0143 >0.9999 >0.9999 0.0143 0.0143 0.0143
(50.2e65.5) (100.0e100.0) (100.0e100.0) (79.8e87.1) (83.5e89.5) (34.5e49.8)
(54.1e69.2) (100.0e100.0) (100.0e100.0) (81.2e88.2) (84.8e90.6) (30.8e45.9)
Numbers in parentheses are 95% confidence intervals. PPV, positive predictive value; NPV, negative predictive value; FNR, falsenegative rate.
The sensitivity, specificity, PPV, NPV, FNR, and accuracy of US and US-FNA with MRI were 61.6% (98/159), 100% (338/ 338), 100% (98/98), 84.7% (338/399), 38.4% (61/159), and 87.7% (436/497), respectively. By adding breast MRI, the sensitivity and NPV increased, whereas FNR decreased (42.1% to 38.4%, p ¼ 0.0143; Table 1, Fig 2).
False-negative nodal disease detected through US and US-FNA with MRI Of the 497 patients included in the study, 399 patients were negative for ALNM on US and US-FNA with MRI. Among these, 61 patients were confirmed to have falsenegative nodal disease with US and US-FNA with MRI. Among 61 patients, six (1.5%) were classified as having Stage N2 disease (range 4e6, median 5.5, maximum size 8 mm), and two (0.5%) were classified as having Stage N3 disease (range 10e18, median 14, maximum size 12 mm; Fig 3). All of these false-negative N2 and N3 disease cases were located at Level 1 of the axilla. Seven out of eight cases of false-negative ALNM were 3e8 mm in size, below the positive MRI criteria in the present study. Only one was >10 mm, but it was classified as clinically N0 because of negative cytology results. The NPV of US and US-FNA with added MRI for excluding N2 and N3 disease was 98% (391 of
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399). The characteristics of false-negative N2 and N3 disease are shown in Table 2.
Discussion In breast cancer patients, preoperative detection of ALNM is important because it determines the treatment and surgery options available to patients.1,2 Currently, US and US-FNA are widely accepted as preoperative diagnostic tools for evaluation of ALNM because of their low morbidity, cost effectiveness, and high diagnostic performance.4,5,7,15 However, these studies also have a variable range of FNR (5e79%) according to the characteristics of the population enrolled, interobserver variability for the detection of potentially metastatic ALNs, and the expertise of the technician performing US-FNA. In cases of false-negative ALNM diagnosed through US and US-FNA, patients might undergo unnecessary SLNB for evaluation of ALN status. Furthermore, patients might be deprived of the opportunity to select other treatment options, such as NAC, prior to surgery. The FNR has been reported to depend on various clinicopathological factors, such as palpability and US findings of ALN, the grade of the primary breast tumour, the number of underlying metastatic ALNs, and the types of primary breast cancer included.15e24 The FNR of US-FNA only accounted for 5e10% of clinically palpable ALNs15 compared to the 37e79% of clinically negative (non-palpable and having at least one suspicious US feature) false-negative ALNs.15,17,19,20,23,24 In the present study, the FNR of US and US-FNA (42.1%, 67 of 159) was within the lowest range of values reported for FNR in clinically negative ALNs. Moreover, the FNR was further improved to 38.4% by the addition of breast MRI (42.1% versus 38.4%, p ¼ 0.0143). The criteria for diagnosing ALNM using breast MRI includes the morphology, number, and size of LNs, and kinetic information using dynamic study. However, these criteria are not yet well established. Accordingly, the predictability for ALNM using MRI is still under debate.5 In the present study, the morphology and size criteria were applied. With
Figure 2 A 48-year-old woman with a palpable mass in the right breast. Initial US identified a suspicious palpable mass but showed no pathological ALNs in the ipsilateral axilla. The mass was confirmed to be invasive ductal carcinoma (IDC) by US-guided biopsy. (a) At MRI, the contrast-enhanced T1-weighted fat-suppression images showed a 2 cm mass in the right upper outer breast, confirmed to be IDC. (b) A round ALN (arrow), suggesting possible metastasis, was seen at Level 1 of the right axilla. (c) Second-look US was performed on the right axillary region and a corresponding suspicious round ALN was noted. US-FNA confirmed the lesion to be a metastatic ALN, and ALND confirmed the diagnosis.
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Figure 3 A 40-year-old woman with a palpable mass in her right breast. The mass was confirmed to be IDC with US-guided biopsy. (a) Initial US revealed a thin, concentric cortex and prominent fatty hilum in the ipsilateral axilla (arrows). (b) At MRI, contrast-enhanced T1-weighted fatsuppression imaging showed an irregularly shaped mass in the right upper breast, which was confirmed to be IDC. (c) Contrast-enhanced T1weighted sagittal image showed only benign-looking ALNs in the right axilla (arrows). (d) Contrast-enhanced T1-weighted coronal imaging showed no pathologically enlarged ALNs in the right axilla (circle). There were no suspicious features suggesting metastasis. However, final histopathology revealed metastatic carcinoma in 10 out of 10 ALNs, with the largest measuring 7 mm, suggesting advanced N3 disease.
Table 2 False-negative N2 and N3 disease detected using ultrasound (US) and US-fine-needle aspiration (FNA) with added magnetic resonance imaging (MRI). Case no.
Age (years)
T-staging
N-staging (number of ALNM)
Maximum size of ALNM (mm)
Histological type
1 2 3 4 5 6 7 8*
46 42 63 45 56 25 40 54
T2 T2 T2 T1c T2 T1c T2 T1c
N2 N2 N2 N2 N2 N2 N3 N3
3 5 6 7 8 4 8 12
Mixed invasive lobular and ductal carcinoma IDC IDC IDC IDC IDC IDC Invasive apocrine carcinoma
(6) (6) (4) (7) (6) (5) (10) (18)
ALNM, axillary lymph node metastasis; IDC, invasive ductal carcinoma. * False negative case that showed positive findings on US and MRI, but classified as clinically N0 because of negative cytology result.
the morphological criteria used in the present study, Fernandez et al.5 suggested that axillary MRI did not improve the preoperative work-up, as it had only 36% sensitivity for detecting ALNM in breast cancer patients. Although the generalization of the present study was limited by application of breast MRI to only one-fifth of the study population and the ambiguity of their indications for breast MRI, 36% was a much lower sensitivity than expected. When kinetic analysis of lymph node enhancement and specially designed breast coils to cover the axillary area were included, the sensitivity and specificity of axillary MRI were greatly improved to 83% and 90% in the study of Kvistad et al.25 However, their study still involved falsepositive detection of benign LNs with abnormal increases in signal intensity (SI). Benign lymph node disease, such as lymphoid hyperplasia, has been reported to show rapid enhancement on MRI in other studies.26
Mortellaro et al.10 suggested that criteria including the number of ALNs and the loss of fatty hilum were more useful than kinetic analysis of ALNs for the diagnosis of metastasis.10 They suggested that breast MRI may provide radiologists the chance to confirm ALN status without additional invasive procedures. This extra step can prevent unnecessary SLNB in cases with positive results, which was consistent with the present results. Their criteria were not analysed for false-positive interpretation of MRI, which was then proven negative through second-look US (n ¼ 3) and second-look US with FNA (n ¼ 10, Fig 1). However, in the present study, information regarding previous axillary US and US-FNA was provided during the interpretation of axillary MRI, which prevented the study of sensitivity and specificity of breast MRI alone. Although the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial suggested that intensive
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therapy, such as complete axillary dissection, may not be beneficial in cases of minimally invasive N1 disease,27 results were limited in cases with breast-conserving surgery. The understanding of whether N2 or N3 can be excluded using breast US or another imaging method is important for the determination of surgical extent. Based on this suggestion, Neal et al.28 reported that preoperative US can exclude 96% of N2 or N3 disease. However, their study was based only on US, which is non-invasive, but well-known for high interobserver variability, limiting its generalizability in practice at this time. In the present study, US and US-FNA were used, the most widely accepted techniques for preoperative axillary staging. Although more invasive than US alone, this combination can confirm cytological metastasis with objective proof and show excellent PPV up to 100%, much higher than that of US alone (66.7%, 106 of 159 in Fig 1). This may obviate the need for SLNB in cases with cytologically proven metastasis. In the present study, breast MRI was performed without any additional burden on the patient because all patients with breast cancer underwent breast MRI for the evaluation of disease extent during the study period. Although it could not be demonstrated how many cases of N2 or N3 disease were excluded by MRI, axillary evaluation using breast MRI may be a useful adjunct because MRI is an objective method of counting nodes and is easy to generalize. The present findings suggest that axillary US and US-FNA with MRI can almost entirely exclude advanced N2 and N3 disease in invasive breast cancer patients with a NPV of 98%. With only six extra ALNM identified by added MRI, breast MRI may not be considered to be cost effective if it were performed only for axillary evaluation; however, added MRI is valuable for the detection of abnormal ALN as appropriate treatment plans can be formulated when breast MRI is performed for preoperative evaluation. The present study has several limitations. First, nine different radiologists with varying degrees of experience performed axillary US and US-FNA, and therefore, interobserver variability may have affected the results. Second, MRI was performed as the last diagnostic examination; therefore, these results may have been influenced by previous US and US-FNA results. Third, in the authors’ institution, most patients who were confirmed to have ALNM underwent NAC. In these cases, surgery was performed after NAC. Therefore, the number of patients who initially had N2 or N3 disease could not be evaluated, because after NAC, proven metastatic ALNs were converted to negative. In the same manner, additional detection of N2 or N3 disease by the addition of MRI could not be evaluated. Fourth, all breast MRI examinations were reported by one radiologist with 10 years of experience, so generalization of the results is limited and further evaluation is needed. In conclusion, breast MRI in combination with US and US-FNA increases sensitivity and decreases FNR while retaining high specificity, because it provides an opportunity to re-evaluate ALNs. This additional imaging technique will help determine the optimal treatment approach in breast cancer patients.
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