What is a stable intramammary lymph node

The purpose of this study was to describe MRI features of malignant and benign IMLNs and to determine the most effective parameter for detecting metastatic IMLNs in breast cancer patients.

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METHODS

This study was approved by Seoul St. Mary's Hospital Institutional Review Board (KC15RISI0092) and the need for informed consent was waved.

Patients

Based on a review of breast MRI records from May 2009 to December 2014, 85 patients with IMLNs were identified. Twenty-six patients were excluded because the lesions were too small (long axis diameter <5 mm) to characterize. The remaining 59 patients were classified into the malignant IMLN group (n=40) or benign IMLN group (n=19). This classification procedure was achieved in several ways. In 10 cases, benignity (n=1) and malignancy (n=9) were determined using pathologic examination. If pathologic examination was not performed, benign IMLNs were defined as showing 1 year of stability on MRI or no fluorodeoxyglucose (FDG) uptake on positron emission tomography computed tomography (PET/CT) (n=18). In contrast, malignant IMLNs were defined as showing FDG uptake greater than that of the adjacent background activity (determined in regions such as the pectoralis muscle, the intercostal space along the lateral sternal border or the mediastinal blood pool), increased FDG uptake on follow up PET/CT, an increased in size during the follow-up period, or a decrease in size after chemotherapy or radiation treatment (n=31) [7, 10].

Patient pathologic and medical reports were reviewed for tumor size, axillary lymph node (LN) status, and distant metastasis.

MRI technique

MRI was performed in the prone position using a dedicated bilateral breast surface coil. Imaging with a 3T MRI system (Verio; Siemens Healthcare, Erlangen, Germany) was obtained using the following sequences: (1) an axial, turbo spinecho T2-weighted imaging sequence with repetition time/echo time (TR/TE) of 4,530/93, flip angle of 80°, 34 slices, field of view (FOV) of 320 mm, matrix size of 576×403, 1 number of excitations (NEX), slice thickness of 4-mm and acquisition time of 2 minutes 28 seconds; (2) axial diffusion weighted imaging (DWI) with two sequences (i.e., single-shot echo planar image [ss-EPI] or readout segmented EPI [rs-EPI]) (b values, 0 and 750 s/mm2; TR/TE, 9,800/87 ms and 5,600/55 ms, respectively; FOV, 340×117 mm and 360×180 mm, respectively; matrix size, 192×82; slice thickness, 4 mm; acquisition time, 2 minutes 47 seconds and 2 minutes 31 seconds, respectively; and 5 readout segments for rs-EPI). Apparent diffusion coefficient (ADC) maps were calculated automatically using MRI software from DWI; and (3) pre- and postcontrast, volumetric interpolated breath-hold examination sequences with a TR/TE of 4.4/1.7, flip angle of 10°, slice thickness of 1.2-mm and acquisition time of 1 minute. The images were obtained before and at 10, 70, 130, 190, 250, and 310 seconds after an injection of contrast agent gadolinium-DTPA (Gd-DTPA, 0.1 mmol/kg Gadovist; Bayer Schering Parma, Berlin, Germany). Imaging performed with a 1.5T MRI system (Signa; GE Medical Systems, Milwaukee, USA) was conducted using the following sequences: (1) axial, fat-suppressed, fast spin-echo T2-weighted imaging (TR/TE=4,000/85, flip angle of 90°, 30 slices, FOV of 240 mm, matrix of 256×224, NEX of 2, 3-mm slice thickness with 0.1-mm slice gap and acquisition time of 2 minutes 56 seconds); (2) axial DWI with ss-EPI (b=0 and 1,000 s/mm2, TR/TE=6,000/75, FOV of 360 mm, matrix of 128×128, 2 NEX, 4-mm slice thickness with 1-mm slice gap, and acquisition time of 1 minute 30 seconds); and (3) preand postcontrast, axial spin-echo T1-weighted imaging (TR/TE=6.2/3.1, flip angle of 10°, 2.6 mm section thickness, FOV of 300 mm, matrix of 256×192, and acquisition time of 1 minute 31 seconds) obtained before and 91, 192, 273, 364, and 455 seconds after the rapid bolus injection of Gd-DTPA.

The images were retrospectively reviewed by two experienced breast radiologists and a consensus was agreed concerning the following parameters: (1) long and short axis length; (2) short diameter/long diameter (S/L) ratio; (3) presence of fatty hilum; (4) multiplicity; (5) intercostal space location; and (6) signal intensity on diffusion weighted image and ADC map. For measurement of LN size both sagittal and axial images were evaluated and the largest and the smallest lengths were measured using the magnified images on dedicated software (Aquarius iNtuition; TeraRecon Inc., Foster City, USA).

Statistical analysis

Differences in age, tumor size, short axis length of IMLN, long axis length of IMLN, and S/L ratio were tested using the independent-sample t-test. Differences in distant metastasis, fatty hilum, intercostal space, and signal intensity in DWI and ADC maps were tested using the Mann-Whitney U test (if the number in a cell was ≤5). Differences in axillary metastasis, LN multiplicity, and tumor location were tested using Pearson chi-square test.

A parametric estimate of the area under the receiver operating characteristic (ROC) curve was used to compare the diagnostic ability of variables to differentiate benign and malignant lymph nodes. The optimal cutoff value was determined according to the Youden index (J), and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. All statistical analyses were performed using the statistical software package SPSS version 19.0 (IBM Corp., Armonk, USA). A p-value < 0.05 was considered statistically significant.

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RESULTS

Patient characteristics

Patient characteristics are summarized in Table 1. Of all the parameters measured, only axillary LN metastasis was significantly different between benign and malignant internal mammary lymph node groups (p<0.05). Positive axillary lymph nodal involvement of the malignant and benign groups was 85.0% and 52.6%, respectively. The other characteristics were not significantly different between the two groups (Table 1).

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Positive distant metastasis such as liver, bone, lung, brain, contralateral IMLN and contralateral axillary LN of the malignant and benign groups was 32.5% and 26.3%, respectively.

In PET/CT, the mean maximum standardized uptake value of metastatic IMLNs was 4.78±3.32. No FDG uptake was observed in the benign IMLNs.

MRI findings

The relevant measurable characteristics obtained from the MRI findings are summarized in Table 2.

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Of the parameters measured, short and long axis length, absent fatty hilum and restricted diffusion (p<0.001 for each), and S/L ratio (p=0.041) were all significantly different between the two groups. In the malignant IMLN group, the mean short axis length of enlarged nodes was 8.2±2.9 mm and the mean long axis length was 14.5±4.8 mm; the S/L ratio was 0.59±0.17. Most cases lost fatty hilum (95.0%), and showed restricted diffusion (85.0%) (Figure 1, 2). In the benign IMLN group, the mean short axis length was 3.6±1.3 mm and the mean long axis length was 8.1±2.4 mm; the S/L ratio was 0.45±0.10. All cases preserved fatty hilum (100.0%) and most did not show restricted diffusion (68.5%) (Figure 3, 4). In both groups, the majority showed single node involvement (65.0% and 68.4% for malignant and benign groups, respectively) located at the second intercostal space (42.5% and 84.2%, respectively).

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Based on the ROC curves (Figure 5), short axis length was the most discriminative variable for predicting a metastatic node (AUC, 0.951). A short axis length of 4mm was determined as the threshold at which the Youden index reached its peak. At the determined threshold, the sensitivity, specificity, PPV, and NPV were 92.5%, 84.2%, 92.5%, and 84.2%, respectively. The AUC of long axis length and S/L ratio were 0.906 and 0.756, respectively. The thresholds for each parameter and the sensitivity, specificity, PPV, and NPV at the adopted thresholds are summarized in Table 3.

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DISCUSSION

Our study evaluated the ability of MRI features to discriminate between malignant and benign IMLNs in breast cancer patients. Short axis length, long axis length, S/L ratio, absent fatty hilum, and restricted diffusion were discriminative variables for predicting metastatic nodes. Among these, short axis length was the most discriminative variable. The optimal threshold to predict metastasis was 4 mm for short axis length and 10 mm for long axis length, respectively. Kim et al. [11] reported optimal thresholds for short and long axis lengths of axillary LN as 9.3 mm and 11.3 mm, respectively. In the present study, the short axis length was considerably shorter than that of axillary LN and the long axis length was slightly shorter than that of axillary LN. In recent studies of normal internal mammary lymph nodes incidentally detected on breast MRI, the average long axis diameter was 4.5 mm (range, 2–9 mm) [12] or 4 mm (range, 3–10 mm) [13].

Mean S/L ratio was higher in malignant nodes (0.59±0.17) than benign nodes (0.45±0.10), and the optimal threshold was 0.5. This finding suggests that benign nodes tend to be more lentiform in shape and malignant nodes tend to be more round. Other studies of axillary LNs have reported a significant difference in the short axis–long axis ratio [14, 15]. He et al. [14] reported that the S/L axis ratio of axillary malignant and benign nodes was, respectively, 0.71±0.12 versus 0.55±0.16 (p<0.001) and the optimal threshold was 0.62.

Fatty hilum was absent in the majority of malignant nodes (95.0%), while all benign nodes (100.0%) preserved fatty hilum (p<0.001). Loss of fatty hilum also varied significantly in other studies of axillary LNs [11, 15, 16, 17].

Diffusion restriction was observed in the majority of malignant nodes (85.0%) and only 15.8% of benign nodes (p<0.001). These results are similar to those of prior studies of axillary LNs [11, 14, 18, 19, 20].

Previous studies have demonstrated that PET/CT is superior to conventional diagnostic techniques for detection of internal mammary LN metastases [21, 22]. An et al. [7] reported that PET/CT-positive internal mammary LNs were defined as those with an uptake greater than the adjacent background activity of the pectoralis muscle or the intercostal space along the lateral sternal border. In their study, there were statistically significant differences in maximum standardized uptake values from PET/CT between the metastatic and benign IMLN groups (p=0.002), the mean maximum standardized uptake value of metastatic and benign IMLNs being 3.53±1.79 and 1.06±1.09, respectively. Seo et al. [10] reported that most metastatic LNs (83.0%) present with a higher intensity of FDG uptake than the mediastinal blood pool, with a maximum standardized uptake of 3.5±4.3. In our study, the mean maximum standardized uptake value of metastatic IMLNs was 4.78±3.32.

For patient characteristics, axillary LN metastasis was significantly different between the two groups (p<0.05). Previous studies report that positivity of axillary nodes is the strongest predictive factor for IMLN involvement [23, 24]. Tumors with a medial location and larger size are associated with a higher rate of internal mammary LN metastases [25, 26, 27, 28]. However, contrary to previous results, medial tumor location and tumor size were not predictive for internal mammary LN metastases in our present analysis. Coombs et al. [29] reported age under 35 years as a risk factor for IMLN involvement. Hence, it is important to note that the patients in our malignant group were older than those in our benign group.

There are some limitations to the present study. First, it was a retrospective study with a small case number. Second, IMLN malignancy was mostly defined by increased maximum standardized uptake value and not by pathology. Third, lymph nodes with a long axis length of less than 5 mm were not included.

In conclusion, MRI parameters including short axis length, long axis length, S/L ratio, absent fatty hilum, and restricted diffusion can be used to differentiate malignant and benign IMLN in breast cancer patients. Among these parameters, short axis length was the most discriminative variable for predicting metastatic nodes.

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