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Detection of axillary lymph node metastasis with diffusion-weighted MRimaging

Mami Iima, Masako Kataoka, Ryosuke Okumura, Kaori Togashi

PII: S0899-7071(14)00117-XDOI: doi: 10.1016/j.clinimag.2014.04.016Reference: JCT 7618

To appear in: Journal of Clinical Imaging

Received date: 8 January 2014Revised date: 26 March 2014Accepted date: 23 April 2014

Please cite this article as: Iima Mami, Kataoka Masako, Okumura Ryosuke, TogashiKaori, Detection of axillary lymph node metastasis with diffusion-weighted MR imaging,Journal of Clinical Imaging (2014), doi: 10.1016/j.clinimag.2014.04.016

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Detection of axillary lymph node metastasis with diffusion-weighted MR imaging

Mami Iima1,2*

, Masako Kataoka1, Ryosuke Okumura

2, Kaori Togashi

1

1Dept of Diagnostic Radiology, Kyoto University Graduate School of medicine, Kyoto,

JAPAN.

2Dept of Radiology, Kitano Hospital, Osaka, JAPAN.

*CA: Mami Iima

Dept of Diagnostic Radiology, Kyoto University Graduate School of medicine, 54 Shogoin

Kawaharacho, Sakyoku, Kyoto, 606-8507 JAPAN

Phone: +81-75-751-3760, FAX: +81- 75-771-9709

e-mail: mamiiima@kuhp.kyoto-u.ac.jp

The authors declare that they have no conflict of interest.

Manuscript type : Full-length article

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Abstract

The feasibility of detecting axillary lymph node (LN) metastases with diffusion-weighted MR imaging was

retrospectively evaluated. The relative ADC (with b values of 0 and 1,000 sec/mm2) between LNs in each

axillary space was calculated (n=75). The area, the long and short diameter of the metastatic LNs were

compared to those of non-metastatic LNs. The relative ADC value of metastatic LNs was siginificantly

lower than those of non-metastatic LNs (P=0.00). The long and short diameter LN diagnostic performance

was superior to that of mean ADC and relative ADC (AUC: 0.84, 0.80 versus 0.64, 0.03), suggesting

usefulness of diameter over ADC.

Keywords:

Breast cancer, axillary lymph node, diffusion-weighted image, apparent diffusion coefficient

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Introduction:

The breast cancer is the most common cancer diagnosed in woman worldwide, and approximately

39,510 women will die of breast cancer in the United States in 2012 (1). Evaluation of sentinel

axillary lymph node status is the most important factor determining prognosis of breast cancer (2),

and the presence or not of axillary lymph node metastases in breast cancer patients is a central issue

to determine the surgical and accompanying procedure (chemotherapy, radiotherapy or neoadjuvant

chemotherapy). To be of value for clinical decision making, the accuracy of any imaging modality

which is used to assess lymph-node status must closely match histopathologic findings. Computed

tomography (CT), ultrasonography (US), positron emission tomography (PET), and MR

lymphography with gadolinium compounds or an ultrasmall superparamagnetic iron-oxide

nanoparticle have been proposed to evaluate the presence of lymph node metastases (3, 4). Korteweg

et al. have succeeded in depicting healthy axially lymph nodes well correlated with pathology by

high resolution 7 Tesla MRI (5). But at present, the differentiation of benign from malignant nodes

still relies on the size and shape of a lesion, and preoperative assessment of lymph-node status is

limited. So far as known, there is no global consensus with regards to the optimal diagnostic method

for lymph node staging. FDG-PET has relatively high specificity and predictive value for axillary

lymph node staging, (but they are not widely available and can be expensive,) but would be difficult

to replace sentinel lymph node biopsy in patients with breast cancer (6, 7). Diffusion-weighted MR

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imaging has successfully been introduced to detect lymph nodes and more recent studies indicate the

potential of diffusion-weighted imaging as a detection of lymph nodes, but there was a significant

overlap between benign and malignant lymph nodes, insufficient to testify the differentiation

between them so far and unlikely to be useful in clinical practice (8-12). Hence, surgery still remains

the gold standard for lymph-node staging in breast cancer patients. The use of a lymph node specific

MR contrast looks promising, but has not yet entered clinical practice (13).

The purpose of this study was therefore to assess the clinical usefulness of detecting axillary lymph

node metastases with diffusion-weighted MR imaging compared with the conventional size criteria.

Material and Methods

Study patients

Our institutional review board approved the study and patient informed consent was waived

because of the retrospective design. We retrospectively reviewed consecutive breast MRI

examinations performed from July 2008 to April 2010. The subjects comprised 75 female patients

who had with breast cancer. 25 patients were excluded; 8 patients had neoadjuvant chemotherapy

before the surgery, 14 patients were with insufficient MRI images, and the axially lymph nodes for 3

patients were not identified on MRI image. Accordingly, 50 patients (12 patients with metastasis and

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38 patients with non-metastasis) were included for the analysis. A consensus reading between

pathologists, surgeons, and radiologists was performed, to provide the most accurate assignment

between MRI and histopathology. For the metastatic cases, we extracted only defined metastatic

lymph nodes on MRI. After the discussion with pathologists and surgeons, 6 out of 12 patients and 9

lymph nodes with metastasis were proven to be identified on both MRI and pathological result. Out

of 9 metastatic lymph nodes, 7 lymph nodes were from invasive ductal carcinoma, one lymph node

was invasive lobular carcinoma, and one lymph node was from micropapillary carcinoma. Finally,

44 patients (mean age: 57 years; range: 35-79 years; 6 patients with metastasis and 38 patients with

non-metastasis) were included in this study (Figure 1). Characteristics of the lymph nodes, lesions,

and patients evaluated are summarized in Table 1. After initial MRI examination, all patients

underwent surgical resection and received definite pathological diagnosis. All pathological results

were defined according to Tumours of the Breast and Female Genital Organs (14).

MRI acquisition

Breast MR imaging was performed using a 1.5T MRI system (Intera and Achieva, Philips

Healthcare, Eindhoven, The Netherlands) equipped with a dedicated four-channel breast array coil.

The following images were acquired after getting localizers: bilateral sagittal fat-suppressed

T2-weighted images (TR/TE, 4937/90 ms; field of view, 20cm; matrix, 256 × 256; slice thickness, 4

mm; time of acquisition, 162 seconds), fat-suppressed, diffusion-weighted echo-planar imaging

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(EPI) (TR/TE, 8000/96 ms; field of view, 40 cm; matrix, 128 × 104 interpolated to 256 × 256, i.e.

1.56 × 1.56 mm resolution; parallel acquisition factor, 2; slice thickness, 5mm; time of acquisition,

182 seconds; motion probing gradient pulses were applied along the x, y, and z directions with b

values of 0 and 1000 sec/mm²) and free-breathing dynamic contrast-enhanced MRI, which was

conducted using a 3D fat-suppressed T1-weighted gradient-echo sequence (TR/TE, 6.1/3.5 ms; flip

angle, 15°; field of view, 40 cm; matrix, 400×400; slice thickness, 2 mm; reconstructed to 0.78 ×

0.78 × 1 mm resolution; time of acquisition, 255 seconds) that were acquired before and

immediately after contrast agent infusion of Gadoteridol (Gd) (0.2mL/kg, ProHance®, Braco-Eisai,

Tokyo, Japan). T1-weighted images were also acquired 9 minutes after infusion, but those images

were not considered in this study. Central k-space data were acquired first to catch early contrast

enhancement. With DWI data, quantitative diffusion (ADC) images were also calculated on a

voxel-by-voxel basis as: ADC = (1/b) × ln (S0/S) where S0 and S are the signal intensities of each

voxel obtained with the b values of 0 and 1000 sec/mm², respectively.

Data post-processing

1 to 5 lymph nodes could be recognized in each axillary space (left and right) on the DW images (b

= 1000 sec/mm²), and regions-of-interests (ROIs) were drawn manually on the DW images (b =

1000 sec/mm²) as a reference of contrast-enhanced images by an experienced radiologist. ROIs were

defined as slightly smaller than the actual nodes in order to reduce partial volume effects. The

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identified ROIs were then copied and pasted onto the corresponding ADC map for quantitative

analysis. For each ROI, minimum-, mean-, and maximum ADC value (min ADC, mean ADC, and

max ADC), long-axis diameter, short-axis diameter and ROI surface (node area) were extracted. All

lymph nodes that were 7 mm or more in the long-axis diameter on axial images were evaluated. The

mean ADC values of all ROIs each side per patient were averaged. The mean ADC difference

between the lymph nodes in each axillary space (metastatic side – non metastatic side or tumor – non

tumor side in patients without metastasis) was calculated as relative ADC. The statistical

significance of the difference between the ADC values, the size, and the diameter in metastatic and

non-metastatic lymph nodes was assessed using Mann-Whitney test: P < 0.05 was considered

statistically significant. All the statistical analysis was conducted using STATA version 8 (Stata

Corporation, College Station, Texas).

Results:

Pathological survey revealed that none of these lymph nodes has necrosis. The example of the

axillary lymph node and the ROI on DW image is shown in Figure 2. The ADC difference for

patients with and without metastases are shown in Figure 3, Table 2 and Table 3.

The relative ADC value of metastatic lymph nodes was siginificantly lower than those of

non-metastatic lymph nodes (-0.457 x 10 -3

mm²/sec ± 0.186 versus -0.219 x 10 -3

mm²/sec ± 0.214)

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(P = 0.00), although the area under the curve (AUC) of ROC analysis was low (0.03; 95%

confidence interval: 0.00-0.07). There was no significant difference of mean ADC value between

metastatic lymph nodes and benign lymph nodes, however, AUC was relatively high compared to

that of relative ADC (0.64; 0.46-0.82).

The size and diameter difference for patients with and without metastases are shown in Table 2 and

Table 3.

The mean size of metastatic lymph nodes (and their standard deviation) was 115.56 ± 66.73 mm2,

and that of non-metastatic lymph nodes was 56.03 ± 22.16 mm2. There was a significant difference

for the nodal area between metastatic and benign lymph nodes (P = 0.01). An area under the curve of

ROC analysis for the nodal size was 0.77 (0.53-1.00). Both of the long and short axis of the

metastatic lymph nodes were significantly longer than those of non-metastatic lymph nodes (P =

0.001 and 0.004). An area under the curve of ROC analysis for the long and short diameter size was

0.84 (0.64-1.00) and 0.80 (0.61-0.99), respectively.

Discussion:

This study shows that there is a significant difference of the relative ADC value, not the mean ADC,

between metastatic patients and non-metastatic patients, although AUC was not high (0.03). The

nodal size demonstrated better diagnostic performance compared with the relative and mean ADC.

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So far as we know, this is the first trial for evaluating metastatic axillary lymph nodes by using the

relative ADC subtraction value of DW-MRI.

MRI is a useful diagnostic method for identifying axillary lymph node involvement with accurate

evaluation of nodal size and shape, but MRI without DWI was significantly limited due to the poor

detection of metastatic nodes with normal size (15). Previous studies have reported the importance

of DW-MRI in the assessment of axillary lymph node metastasis (9, 11, 12).

According to Guo et al, ADC values of metastatic nodes in cervical and uterine cancers were

normalized with the relative ADC, which subtracts the mean value of tumor from lymph node,

assuming that the metastatic region of the lymph nodes would demonstrate similar cellularity to the

primary tumor (16). Hence, we applied it to our ADC value estimation approach, which would

normalize the ADC value of metastatic lymph nodes. Luo et al. has used ADC ratio between axillary

lymph node and breast carcinoma for differentiating metastatic from benign node (12). Although

they also found the significant difference of mean ADC, which is contrast to our result, such a

different ADC estimation approach might be useful with a larger studies in future.

The newer methods such as USPIO–enhanced MR imaging and PET-CT seem to improve the

preoperative diagnostic accuracy of metastatic lymph nodes compared to conventional imaging (17,

18), but they are expensive and have the risk of contrast enhancement or radiation exposure,

different from DWI. Also, the identification of metastatic lymph nodes based on MR morphological

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criteria still remains challenging, especially for USPIO-enhanced MR imaging (19, 20).

There was a significant difference between axillary lymph node size and the presence of metastasis

(p = 0.01). The size of 2 metastatic lymph nodes was relatively large (239 mm² and 195 mm²,

respectively), and the other case was diagnosed as microinvasion. A previous study has shown that

the size of nodal involvement was significantly correlated with prognostic features (21), but it’s still

clinically unclear to prove the metastatic nodal presence only with size criteria (22). More detailed

morphological investigation, such as cortical thickness, combined with DW-MRI also suggests high

accuracy in the preoperative evaluation of axillary lymph node metastases (9). Considering the

promising results of the diagnostic accuracy of axillary lymph node metastasis using DW-MRI by

the previous studies (10, 12) and the significant difference for relative ADC between metastatic and

benign lymph nodes in our study, we might improve the diagnostic ability with the combination of

DWI and size criteria in future.

Our study confirms that size is more valuable criterion as a detection of axillary lymph node

metastasis compared to ADC, which is in accordance with the previous literature (9). DWI is

suffered from distortion artifact, especially for the small axillary lymph nodes which are situated

near the border of FOV (field of view). DWI is also influenced by many nodal changes; T2 shine

through and blackout effects, necrotic areas, inflammatory nodal hyperplasia accompanied by

increased cellularity, and nodal heterogeneity may cause changes of signal intensity on DWI. Hence,

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these changes would cause ADC artifact and might not reflect the microstructure of the lymph node.

It’s essential to use the methods which will offer better image distortion or signal-to-noise ratio to

overcome these shortcomings of DWI. Moreover, mode detailed information in addition to size

criterion and ADC, such as cortical thickness, might improve diagnostic ability for differentiating

metastatic axillary lymph nodes (12).

One of our limitations is that the only one-side axillary lymph node metastasis was evaluated for

relative ADC (metastatic side – non-metastatic side or tumor – non tumor side in patients without

metastasis); this relative ADC method might not be applied to the cases of bilateral metastasis or

post operation.

In our limited experience, we conclude that the diameter of the lymph node is more useful for the

diagnosis of axillary lymph node metastasis than ADC derived from DWI.

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Table 1. Number of evaluated lymph nodes, lesions and patients according to histopathological

findings.

Lymph nodes (n=91) sides (n=46) patients (n=44)

IDC 67 33 32(31)*

ILC 5 3 2(3)*

DCIS 15 7 7

LCIS 2 1 1

Micropapillary carcinoma 1 1 1

Inctracystic papillary carcinoma 1 1 1

IDC, Invasive ductal carcinoma; ILC, Invasive lobular carcinoma; DCIS, Ductal carcinoma in situ

*2 patients had bilateral cancer; one patient with IDC on both sides, and one patient with IDC on left

side and ILC on right side. There was no lymph node metastasis in these two patients.

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Table 2. Morphologic Features and ADC Characteristics per Node Basis with Metastasis.

Mean SD§ Min Max

area (mm2) 115.6 66.7 27 239

long diameter (mm) 17.7 5.7 7.2 26.1

short diameter (mm) 10.7 4.2 4.6 17.4

mean ADC (10-3

×mm2/sec)* 0.969 0.142 0.784 1.215

relative ADC (10-3

×mm2/sec)

† -0.457 0.186 -0.861 -0.243

§SD = standard deviation

*The mean ADC values of all ROIs each side per patient were averaged.

†The relative ADC was calculated as mean ADC difference between the lymph nodes in each

axillary space (metastatic side – non metastatic side).

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Table 3. Morphologic Features and ADC Characteristics per Node Basis without Metastasis.

Mean SD§ Min Max

area (mm2) 56.0 22.2 27 144

long diameter (mm) 10.9 3.0 4.5 21

short diameter (mm) 6.7 1.7 3.5 11

mean ADC (10-3

×mm2/sec)* 0.907 0.162 0.499 1.302

relative ADC (10-3

×mm2/sec)

† -0.022 0.214 -1.145 0.250

§SD = standard deviation

*The mean ADC values of all ROIs each side per patient were averaged.

†The relative ADC was calculated as mean ADC difference between the lymph nodes in each axillary

space (tumor – non tumor side in patients).

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Figure Legends

Figure 1. Inclusion and exclusion criteria of the patients and axillary lymph nodes.

Figure 2. MR images in breast of 67-year-old woman with primary invasive ductal carcinoma.

Left axillary lymph node is detected on the contrast enhanced T1 weighted image (arrow in (A)) and

DW image with b value of 1000 sec/mm² (arrow in (B)).

Figure 3. Comparison for mean ADC and relative ADC between metastatic and non-metastatic

lymph nodes.

Box plots of mean ADC (A) show a significant overlap between metastatic and benign lymph nodes,

while relative ADC (B) demonstrate a significant difference between them.

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Figure 1

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Figure 2

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Figure 3