Role of diffusion-weighted MRI: predicting axillary lymph node metastases in breast cancer

Abstract

Background

Ultrasound (US) is probably the standard imaging procedure in most centers, and US-guided fine needle aspiration can be added if suspicious lymph nodes are found. However, US-guided fine needle aspiration is an invasive method to diagnose a metastasis and has showed relatively low sensitivity. In general, diffusion-weighted (DW) magnetic resonance imaging (MRI) has become an emerging technique for discriminating benign from malignant breast lesions in a short imaging acquisition time.

Purpose

To evaluate the potential for using DW MRI with an apparent diffusion coefficient (ADC) value to predict axillary lymph node metastases in patients with invasive breast cancer.

Material and Methods

This study enrolled 110 axillary lymph nodes from 110 consecutive women who were diagnosed with invasive breast cancer for preoperative breast MRI and US. The largest enhancing ipsilateral axillary lymph nodes were included in this study, and benign and metastatic axillary lymph nodes were compared according to the pathologic reports. The cut-off ADC value to differentiate between benign and metastatic axillary lymph nodes was evaluated with receiver-operating characteristic curve analysis. Diagnostic performance of ultrasound and DW MRI was calculated for enhancing lymph node in dynamic contrast-enhanced MRI.

Results

Nodal metastases were documented in 68 (62%) axillary lymph nodes. The mean size of metastatic axillary lymph nodes was larger than that of benign axillary lymph nodes (15.5 mm vs. 10.9 mm, P < 0.001). The mean ADC value (0.69 × 10⁻³mm²/s) of the metastases was significantly lower than that of the benign axillary lymph nodes (1.04 × 10⁻³mm²/s) (P < 0.001). The ADC value cut-off between metastatic and benign axillary lymph nodes was 0.90 × 10⁻³mm²/s. Using ADC cut-off, sensitivity, specificity, and accuracy of DW MRI were 100%, 83.3%, and 93.6%, respectively. The sensitivity, specificity, and accuracy of US showed 94.1%, 54.8%, and 79.1%, respectively.

Conclusion

DW MRI of axillary lymph nodes can provide reliable information for the differentiation of benign from metastatic axillary lymph nodes in invasive breast cancer patients.

Keywords

Breast cancer magnetic resonance imaging (MRI)diffusion apparent diffusion coefficient (ADC)axillary lymph node ultrasound (US)

Introduction

The accurate prediction of axillary lymph node (ALN) status is essential to make a plan of treatment for patients with breast cancer (1). The presence of metastases in ALN is the most important single predictor of long-term survival in primary breast cancer patients (2).

A variety of methods have been used for the preoperative staging of ALN. Clinical examination, mammography, and ultrasonography (US) have been used to predict ALN status. However, the diagnostic accuracy of predicting ALN metastases has not been satisfactory (3 –5). The reported sensitivities and specificities of axillary US are in the range of 45.2–100% and 50–89%, respectively (6 –9). The overall sensitivity and specificity of fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) for ALN metastases range from 20–100% and 65–100%, respectively (7,10,11). In terms of magnetic resonance imaging (MRI) studies, the enhancement pattern of primary breast cancer after gadopentetate dimeglumine injection has also been noted with metastatic ALN (12 –14). According to previous studies, metastatic ALNs on MRI show eccentric cortical thickening, round shape, a short-axis dimension of 10 mm or larger and irregular margin (12 –14). While the dynamic contrast-enhanced (DCE) MRI has a relatively high sensitivity of 79–100%, the specificity (56–93%) is relatively low (1 –14). Axillary US with US-guided fine needle aspiration (FNA) has become an accepted method of preoperative assessment of the axilla as a means for diagnosing metastases (15 –17). When preoperative US-guided FNA is positive for metastasis, patients are spared an unnecessary sentinel lymph node biopsy (SLNB) and dissection of ALN is performed directly. However, US-guided FNA is an invasive method to diagnose metastases. In addition, the sensitivity of US-guided FNA is relatively low (39.5–86%), although specificity is high (95.7–100%) (8,15 –17).

Diffusion-weighted (DW) MRI is an unenhanced MRI sequence that has shown promising results for discriminating benign from malignant breast lesions in a short imaging acquisition time (18,19). DW MRI might yield information different from and complementary to that obtained with DCE MRI due to its sensitivity to tissue characteristics such as cell density, membrane integrity, and microstructure (20). Previous studies of DW MRI of the breast have shown that the apparent diffusion coefficient (ADC) is significantly lower in malignant tumors than in benign breast lesions and normal tissues (18,19). Recent several studies have showed variable sensitivities (53.8–94.7%) and specificities (77–91.7%) of DW MRI for ALN metastases (21 –23).

However, these recent studies had small numbers of metastatic lymph nodes (19–28 metastatic lymph nodes), lacking in comparison of US features (21 –23). Also, benign ALN can show strong enhancement with wash-out kinetic pattern in DCE MRI (24).Therefore, the purpose of this study was to evaluate the potential of using DW MRI with an ADC value to predict ALN metastases in patients with invasive ductal carcinoma, comparing with US features.

Material and Methods

This retrospective study was approved by our institutional review board, which waived the requirement for informed patient consent.

Patients

Between June 2009 and October 2010, 197 women underwent mastectomy or breast-conserving surgery with SLNB and/or ALN dissection due to invasive ductal carcinomas of the breast at our institute. Of these 197 patients, 190 underwent preoperative breast MRI and US. MRI and US were retrospectively reviewed by two radiologists in consensus (EJS and JC, with 12 and 2 years of experience interpreting breast MR images, respectively). Among them, 87 patients were excluded because they had undergone preoperative MRI at other institutions (n = 7, 3.6%), without having enhancing ALN in their breast MRIs (n = 74, 37.6%), or for the lack of subsequent surgery at our institution (n = 6, 3.1%) (Fig. 1). Ipsilateral ALNs with breast cancer were included in this study. If multiple enhancing lymph nodes had been presented in the same axilla, the largest lymph node was included in this study. Finally, 110 patients (mean age, 49 years; age range, 27–80 years) with 110 ALNs were included in this study.

Fig. 1.

Flowcharts of the study group.

MRI technique

MRI was performed using a 1.5-T system (Magnetom Avanto; Siemens, Erlangen, Germany) in 38 lesions and a 3.0-T system (Intera Achieva; Philips Medical Systems, Best, The Netherlands) in 72 lesions; both systems used dedicated four-channel phased array breast coils (MATRIX Breast Coil, Siemens; SENSE Breast Coil, Philips Medical Systems). Patients were examined in the prone position. The baseline MRI examination for the two systems consisted of turbo spin-echo T1- and T2-weighted sequences, single-shot spin-echo planar diffusion-weighted sequence, and 3D DCE sequence. All pulse sequence parameters are listed in Table 1.

Table 1.

MRI protocols in 1.5 T and 3.0 T units according to sequence.

	MRI acquisition sequences
	Axial TSE T1-w-MRI		Axial TSE T2-w MRI		Axial SSSEP DWI		3D-axial DCE MRI
MR parameter	1.5T	3.0T	1.5T	3.0T	1.5T	3.0T	1.5T	3.0T
Echo time (ms)	11	10	100	100	91	70	1.34	1.67
Repetition time (ms)	500	526	5000	5266	9700	8496	3.7	4.5
Inversion time (ms)	185	65
Flip angle (degree)	12	12
Slice thickness (mm)	3	3	3	3	3	3	1.5	3
Slice gap (mm)	3	3	3	3	4.5	3	1.5	1.5
Slices (n)	48	48	48	48	30	30	88	88
Field of view (mm × mm)	330	200 × 340	330	200 × 340	340	320 × 150	330	340 × 340
Image matrix (mm × mm)	192 × 384	332 × 332	192 × 384	332 × 332	88 × 180	96 × 142	425 × 512	516 × 484
Bandwidth (Hz/pixel)	151	217.8	151	217.8	1634	30.7	410	385.4
Turbo factor	5	3	17	16
B-vales (mm²/s)	0, 1000	0, 1000

3D, three-dimensional; DCE, dynamic contrast-enhanced; DWI, diffusion weighted MRI; SSSEP, single-shot spin-echo planar; T1-w, T1-weighted; TSE, turbo spin-echo.

Before the contrast material injection, DW MRI was performed in the axial plane on both breasts, with the diffusion gradient applied along the orthogonal direction. DW MRI was performed with b values of 0 and 1000 mm²/s, and the mean acquisition time was 170 s.

The DCE sequence was performed with axial imaging, with one as precontrast and five as postcontrast dynamic series performed at 90, 150, 210, 270, and 330 s after contrast injection. The final delayed DCE sequence was also performed with sagittal imaging at 440 s after injection. Gadopentetate dimeglumine (Bono-I; Central Medical Service, Seoul, South Korea) was injected into an antecubital vein with an automated power injector at a dose of 0.1 mmol per kg of body weight and at a rate of 2 mL/s. This was followed by an 18 mL saline flush.

Ultrasound technique

Ultrasound examinations were performed by one of five board-certified radiologists with 1 to 13 years of experience in breast imaging, using 5 to 12 MHz linear probe (iU22, Philips Medical Systems, Bothell, WA, USA).

Imaging analysis

Breast MRI and US were retrospectively reviewed on a picture archiving and communication system workstation monitor by two radiologists in consensus (EJS and JC with 13 and 3 years of experience interpreting breast images, respectively). Both reviewers were blinded to the final pathologic results of the ALNs.

The largest ipsilateral enhancing ALNs on DCE MRI were included in this study. Each lesion was identified both on subtracted DCE MRI and DW MRI. If there were multiple lymph nodes presented in the same axilla, the largest node was selected. Suspicious MR features of ALNs were as follows: eccentric cortical thickenings (3 mm or more, including loss of fatty hilum), round shapes (long/short axis ratio of <1.6), irregular margins and short-axis dimensions of 10 mm or larger (12 –14). If one or more of the above suspicious MR features were present, ALNs were considered as suspicious. ALNs without any suspicious MR feature were considered as benign. The size of each lesion was measured on axial image of DCE MRI and the short axis of ALN was recorded. Suspicious ultrasound features of ALNs were as follows: irregular margins, eccentric cortical thickenings, and loss of fatty hilum and round shape (6 –9). If one or more of the above-mentioned suspicious ultrasound features were present, lymph nodes were considered as suspicious. Absence of ALN or ALN without any suspicious feature on ultrasound is considered as benign lymph node.

Enhancing ALNs on DCE MRI were all detected on DW MRI. Regions of interest (ROIs) in the corresponding area were defined on DWI to include the area of hyperintensity. ROIs were drawn manually to include the entire lymph node using subtracted DCE MRI and DW MRI as a reference. DWI was used to guide the positioning of the ROI within the ALN, and care was taken to avoid inclusion of the adjacent normal tissue. The ADC value was automatically calculated when the ROI was drawn. The measurement of ROI was performed three times per each node and these three measurements were averaged for the mean ADC. The mean ADC of the ROI was determined, and the cut-off ADC value to differentiate between benign and metastatic ALNs was calculated using receiver-operating characteristic (ROC) curve analysis.

All patients also underwent an ultrasound examination prior to the surgery. The US examinations were retrospectively reviewed by a radiologist (CJ). US features of ALNs were recorded. Suspicious US features of ALNs were as follows: irregular margin, round shape, eccentric cortical thickening, and loss of fatty hilum (6 –9). If one or more of above-mentioned suspicious US features were present, ALNs were considered as suspicious. Remainders and absence of ALN were considered as negative group.

Surgery and pathologic review

Surgical and pathological reports were retrospectively reviewed. All patients with invasive ductal carcinoma of the breasts underwent total mastectomy or breast conserving operation. SLNB and/or ALN dissection were performed for all suspicious ALNs. In patients with metastatic ALNs on SLNB, ALN dissection was subsequently carried out.

Pathologic evaluation was performed by one pathologist who had 18 years of experience in breast pathology. All specimens were fixed in formalin, and frozen sections were used for hematoxylin and eosin and immunohistochemical staining. Maximum diameter >0.5 cm of ALNs was serially sectioned transversely; those <0.5 cm were bisected.

Metastatic and benign ALNs were classified according to their surgical pathologic reports.

Statistical analysis

Statistical comparisons were performed using the McNemar or Fisher’s exact test for categorical variables and the Mann-Whitney U test for continuous variables. ROC curves were used to determine the optimal ADC thresholds for discriminating benign and metastatic lymph nodes.

Using ADC cut-off value, true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) of enhancing ALNs were calculated. Diagnostic performance was calculated as follows: sensitivity, TP/(TP + FN); specificity, TN/(TN + FP); positive predictive value, TP/(TP + FP); negative predictive value, TN/(TN + FN); and accuracy, (TP + TN)/(TP + FP + TN + FN).

P < 0.05 was considered to indicate statistical significance. Statistical analyses were performed using statistical software (SPSS, version 17.0, SPSS Inc., Chicago, IL, USA; MedCalc, version 11.4.4, MedCalc Software, Mariakierke, Belgium).

Results

Clinicopathologic features of the largest enhancing axillary lymph nodes

Eighty patients underwent total mastectomies and 30 patients underwent breast conserving surgery due to primary invasive ductal carcinoma of the breast. For final axillary staging, 42 patients underwent SLNB only, 39 underwent ALN dissection only, and 29 underwent both SLNB and ALN dissection.

On the basis of surgical pathologic reports for the largest enhancing ALNs, 68 patients (62%) had truly metastatic ALNs and 42 patients (38%) proved no axillary metastasis. The mean age of patients was 49 years (range, 27–80 years). There was significant difference in mean age between benign (51 years; range, 30–72 years) and metastatic (49 years; range, 27–80 years) lymph nodes (P < 0.001) (Table 2). Of 110 axillary lymph nodes, 33 lymph nodes (30%) were palpable and among them, 84.8% (28/33) of lymph nodes were metastatic. Forty-seven patients (47/110, 42.7%) had multiple enhancing ALNs on DCE MRI. Among them, 43 patients (43/47, 91.5%) had metastatic lymph nodes (Table 2). Multiple (P = 0.020) lymph nodes represented significant characteristics of metastases. These lymph nodes showed eccentric cortical thickenings (29/27), round shapes (16/47), irregular margins (34/47), and over 10 mm of short diameters (36/47) on DCE-MRI. The mean size of primary breast tumor was 27.4 mm (range, 3–90 mm). The primary breast tumor was significantly larger in patients with metastatic axillary lymph nodes (P < 0.001) (Table 2). The clinical mean size of the ALN on DCE MRI was 13.9 mm (range, 5–44 mm), and metastatic lymph nodes were significantly larger than benign lymph nodes (15.5 mm vs. 10.9 mm, P < 0.001). There were no benign lymph nodes in patients with stage T4 breast cancers (Table 2).

Table 2.

Patient demographics and tumor characteristics.

Metastasis	Benign	P value
(n = 68)	(n = 42)	P value
Mean age of patients (years)	48.8 ± 10.3	51.0 ± 11.1	<0.001
Clinical symptom	<0.001
Palpable mass	53	29
Discharge	1	0
Pain	6	1
No symptom	8	12
Palpable axillary lymph node	28	5	0.146
Multiple enhancing axillary lymph node	43	4	0.020
Mean size of breast tumor (mm)	30.4 ± 18.2	22.4 ± 12.2	<0.001
Mean size of lymph node (mm)	15.5 ± 7.7	10.9 ± 4.7	<0.001
Pathologic T stage*
T1	22	21
T2	34	18
T3	8	3
T4	4	0
Pathologic N stage*
0	0	42
1	46	0
2	12	0
3	10	0

By AJCC American Joint Committee on Cancer classification.

Among the 110 enhancing ALNs, 17 lymph nodes were not detected on US. Suspicious US features of ALNs were as follows: irregular margins, eccentric cortical thickenings, loss of fatty hila, and round shapes (6 –9). If one or more of the above-mentioned suspicious US features were present, lymph nodes were considered as suspicious. Absence of ALN or ALN without any suspicious feature on US was considered as benign lymph node. Eighty-three ALNs showed suspicious US features. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of axillary US were 94.1% (64/68), 54.8% (23/42), 77.1% (64/83), 85.2% (23/27), and 79.1% (87/110), respectively.

ADCs of benign and metastatic lymph nodes

The mean ADC of overall ALNs was 0.83 × 10⁻³mm²/s. The mean ADC of metastatic lymph nodes (0.69 × 10⁻³mm²/s) was significantly lower than that of benign lesions (1.04 × 10⁻³mm²/s) (P < 0.001) (Figs. 2 –4). The best ADC cut-off to differentiate metastasis from benign lymph nodes based on ROC curve analysis was 0.90 × 10⁻³mm²/s, and the area under the ROC curve (A_z) for differentiation of benign and metastatic lymph nodes was 0.968 (95% confidence interval, 0.916–0.992) (Fig. 5). The ADCs of all metastatic lymph nodes were <0.90 × 10⁻³mm²/s. However, seven of 42 (17%) benign lymph nodes showed low ADC values (range, 0.72–0.88 × 10⁻³mm²/s).

Fig. 2.

Box and whisker plot of mean ADCs. The top and bottom of each box represent the 25th and 75th percentiles of the ADC, respectively. The horizontal line inside each box represents the median.

Fig. 3.

A 40-year-old woman with a surgically verified metastatic lymph node in the left axilla. (a) Axial early DCE 3D T1-weighted subtraction 1.5-T MR image (1.34/3.7, 12° flip angle) of the left axilla shows a 2.4-cm enhancing lymph node (arrow). (b) Axial single-shot-spin-echo planar DW MR image (9700/185) shows a lymph node as an area of high signal intensity (arrow). (c) Axial ADC map (b values, 1000 mm²/s; 9700/185) shows the same lesion with restricted diffusion (arrow). The region of interest was manually drawn on the ADC map, guided by a DCE MR image. The mean ADC of the lesion was 0.69 × 10⁻³mm²/s, which indicated a metastatic lymph node with a 0.90 × 10⁻³mm²/s ADC cut-off.

Fig. 4.

A 57-year-old woman with a surgically verified benign lymph node in the right axilla. (a) Axial early DCE 3D T1-weighted subtraction 3.0-T MR image (1.67/4.5, 12° flip angle) of the right axilla shows a 1.3-cm enhancing lymph node (arrow). (b) Axial single-shot-spin-echo planar DW MR image (8496/65) shows a lymph node (arrow) as an area of high signal intensity. (c) Axial ADC map (b values, 1000 mm²/s; 8496/65) shows the same lesion with unrestricted diffusion (arrow). The region of interest was manually drawn on the ADC map, guided by a dynamic contrast-enhanced MR image. The mean ADC of the lesion was 1.26 × 10⁻³mm²/s, which indicates a benign lymph node with a 0.90 × 10⁻³mm²/s ADC cut-off.

Fig. 5.

ROC curve for axillary lymph node ADCs used to predict metastasis in 110 patients with invasive breast cancer. The best metastatic ADC cut-off value was 0.90 × 10⁻³mm²/s, and the area under the ROC curve was 0.968 (95% confidence interval, 0.916–0.992).

Addition of ADC cut-off value (0.90 × 10⁻³mm²/s) resulted in sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100% (68/68), 83.3% (35/42), 90.7% (68/75), 100% (35/35), and 93.6% (103/110), respectively.

Discussion

The ALN status is the single most important factor for predicting prognosis of breast cancer patients. Surgical treatment of breast cancer and evaluation of ALN status have become progressively less invasive during the past decades. Complete ALN dissection has been replaced with SLNB, and preoperative imaging studies are currently widely used for staging. However, imaging studies for ALN status are still difficult and have a varied range of sensitivity and specificity (5 –14). For example, US showed a low sensitivity and DCE MRI showed a low specificity for the evaluation of ALNs (6 –9,14). US-guided FNA also showed a low sensitivity (8,15 –17).

To overcome low specificity of DCE MRI, DW MRI has become an emerging imaging technique for differentiation of benign and malignant breast lesions. Recent studies have shown DW MRI being a useful method in the differential diagnosis between benign and metastatic ALNs in patients with breast cancer (21 –23). However, these studies enrolled a small numbers of metastatic ALNs only and all DW MRI studies were performed with a 1.5-T unit. Our study included a large number of patients (68 metastatic ALNs) and applied 3.0-T MRI system. Similar to findings in prior studies, our results showed that metastatic ALNs had significantly lower ADC values than benign ALNs (P < 0.001) (21 –23). Our study showed 100% sensitivity, 83.3% specificity, and 93.6% accuracy with a threshold of 0.90 × 10⁻³mm²/s for the ADC value for metastatic ALNs. Using this ADC cut-off value (0.90 × 10⁻³mm²/s), 26.4% (29/110) of all breast cancer patients with enhancing ALNs could avoid unnecessary SLNB. Park et al. reported that 16.2% of patients could avoid SLNB, after adding US-guided FNA (8). In our study, DW MRI with ADC cut-off value showed higher diagnostic performance than axillary US.

In our study, seven false-positive nodes were found with ADC values lower than the threshold. All of these seven ALNs (range, 6–10 mm) were smaller than the mean benign ALN (10.9 mm). This result indicates that in small ALNs it can be difficult to distinguish between metastatic and benign nodes. Previous studies have shown that there is no correlation between ALN size and the presence of metastases (25 –27). However, another study has shown that a large size (>10 mm) is a predictor of metastasis (13). Our study also showed the metastatic ALNs were larger than benign ALNs (P < 0.001).

Our study had several limitations, including those inherent to a retrospective analysis. First, we did not attempt to match nodes identified on MR images and US images with nodes removed at axillary surgery owing to a loss of anatomical landmarks in the excised tissue. We only included the largest lymph node at the ipsilateral axilla. The second limitation was that we only assessed lesions deemed ALNs with invasive ductal carcinomas of the breast. Our study did not include other malignancies (e.g. ductal carcinoma in situ or mucinous carcinoma), although a previous study has shown a high ADC value for mucinous carcinoma (28). If we had included mucinous carcinomas, our results might have been different. Further studies are needed to enlarge case numbers and address other breast malignancies. Third, there may be potential for criticism regarding the use of either a 1.5- or a 3.0-T MR system in the present study. However, since similar results were obtained with both systems, the results may be applicable for general practice using either system. In addition, a prior study had looked at the visibility of breast lesions detected by MRI, compared the ADCs at 1.5-T imaging with those at 3.0-T imaging in the same patients (16 lesions in 13 patients). The study had concluded that there were no significant differences in the ADCs of small (≤10 mm) and large (>10 mm) benign and malignant lesions between the 1.5-T and 3.0-T MR systems (29). Fourth, we only included enhancing ALNs on DCE MRI. Therefore, non-enhancing ALNs on DCE MRI were not included in this study. These ALNs could make false-negative cases. Finally, the detection of lesion on DW MRI may not always be easy. Artifacts such as motion, susceptibility, or chemical shift are very sensitive in DW MRI, could impair ADC measurements and distort images. In this study, we encountered DW MRI artifacts in two cases only. Although all ALNs were detected both on DW MRI and DCE MRI, two lesions were faintly appeared on DW MRI, due to motion or susceptibility artifacts.

Despite these limitations, our study provides an impetus for further research. In daily practice, suspicious enhancing ALNs were sometimes problematic, due to high sensitivity and low specificity of DCE MRI. Additional DW MRI to DCE MRI may suggest guidelines for these suspicious enhancing ALNs. The mean ADC values of metastatic ALNs were significantly lower than those of benign ALNs, and the mean size of metastatic ALNs was larger than that of benign ALNs. Our results also suggest an ADC cut-off that can be used to discriminate between metastases and benign ALNs.

In conclusion, DW MRI of ALNs in breast cancer can provide reliable information about the axilla lymph node staging in breast cancer patients.

Footnotes

Funding

This research was supported by a faculty research grant of Yonsei University College of Medicine for 2012(6-2012-0020).

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