Characteristics of axillary lymph nodes apparent on dynamic contrast-enhanced breast MRI in healthy women

Clinical Imaging 36 (2012) 249 – 254

Characteristics of axillary lymph nodes apparent on dynamic contrast-enhanced breast MRI in healthy women Julia Krammer a,⁎, Dorothee Engel a , Johanna Nissen a , Andreas Schnitzer a , Marc Suetterlin b , Stefan O. Schoenberg a , Klaus Wasser a a

Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim-University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany b Department of Gynecology and Obstetrics, University Medical Centre Mannheim, Medical Faculty Mannheim-University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany Received 25 October 2011; accepted 22 December 2011

Abstract The study was initiated to characterize and better understand the natural characteristics of axillary lymph nodes (LNs) apparent on dynamic breast magnetic resonance imaging (MRI). The most important finding in 71 subjects that included healthy women was that 41% showed strong enhanced axillary LNs. The dynamic curves of these LNs revealed an initial mean signal increase of 197% (±58%), all of them with a following plateau (34%) or washout (66%). Our study points out that the previous understanding of contrast enhancement in breast lesions should be taken with care when assessing axillary LNs. This has to be considered especially in preoperative breast MRI. © 2012 Elsevier Inc. All rights reserved. Keywords: Dynamic breast MRI; Normal lymph nodes; Axillary lymph node staging

1. Introduction Dynamic contrast-enhanced breast magnetic resonance imaging (MRI) is well known as a sensitive method for the diagnosis of breast cancer and is increasingly used for preoperative evaluation of the tumor extent [1,2]. Beside morphologic criteria, semiquantitative assessment of enhancement kinetics on dynamic breast MRI has been established to differentiate malignant from benign lesions [3–6]. Using standard breast coils, the axillary region is not fully covered and for that reason a complete preoperative assessment of the lymph node (LN) status cannot be assured by dynamic breast MRI alone. Nevertheless, the radiologist is regularly confronted with ⁎ Corresponding author. Institute of Clinical Radiology and Nuclear Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim-University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Tel.: +49 0 621 383 2067; fax: +49 0 621 383 1910. E-mail address: [email protected] (J. Krammer). 0899-7071/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.clinimag.2011.12.022

axillary LNs apparent on preoperative breast MRI as well. An accurate preoperative assessment of axillary LN is necessary since sentinel LN biopsy has been established. A preoperative detection of metastatic axillary LNs makes a following sentinel LN biopsy redundant, and sentinel node biopsy is even contraindicated in this case. Today, ultrasound is still the method of choice for preoperative LN staging [7]. The way to assess axillary LNs on preoperative dynamic breast MRI is still less studied, and most studies performed included small samples [8–10]. In the early era of dynamic breast MRI, Heiberg et al. stated that metastatic LNs have an enhancement profile similar to the one of the primary [10]. To better understand how to interpret axillary LNs on dynamic breast MRI preoperatively and to find out whether the dynamic MRI criteria of breast lesions can be used for the evaluation of axillary LNs as well, we need to know more about the normal findings. To our knowledge, this is the first study dealing with the axillary LN findings on dynamic breast MRI in healthy women.

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2. Methods 2.1. Patients The study was approved by the ethics committee of our university medical center. At the beginning, all patients who obtained dynamic breast MRI at our Breast Centre and whose findings were classified as breast imaging reporting and data system (BI-RADS) 1 or BI-RADS 2 were retrospectively collected by search of the Radiology Information System. The period of acquisition was from 01 January 2005 to 31 June 2010. Any patients with malignancies or systemic inflammatory diseases stated in the case history and findings of our Breast Centre at the time of dynamic breast MRI were excluded from the study as axillary morphology and contrast behavior might have been affected. The patient's health status had to be ensured at our Breast Centre by a follow-up of at least 6 months by clinical or radiological examination. Altogether, a total of 77 patients with BI-RADS 1 or BIRADS 2 were determined without any malignant or inflammatory disease. In the course of the follow-up examinations, two of them were excluded because a ductal carcinoma in situ (DCIS) was diagnosed in one and a nonHodgkin lymphoma was diagnosed in the other. From the remaining 75 patients, four were eliminated because of nonacceptable image quality. The mean characteristics of the 71 remaining patients are shown in Table 1. 2.2. MRI Breast imaging was performed with a 1.5-T system (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) by using a standard bilateral breast coil. The standardized protocol consisted of a T2-weighted turbo spin-echo sequence [3-mm axial slices, field of view 320 mm, matrix 512×512, repetition time (TR)/echo time (TE) 4400/104 ms], a short tau inversion recovery (STIR) sequence (3-mm axial slices, field of view 320 mm, matrix 512×512, TR/TE 5620/84 ms), and a T1-weighted (T1w) 3D gradient-echo sequence (1.6-mm axial slices, field of view 320 mm, matrix

512×512, TR/TE 4/1.5 ms), once before and (for dynamic acquisition) eight times after bolus injection of 0.2 mmol of Gd-DTPA or Gd-DOTA per kilogram of body weight. The temporal resolution was 50 s for each dynamic acquisition. Postcontrast image subtraction was performed to suppress the fat signal. 2.3. Image analysis All breast MRI data were transferred to a workstation which allows the image viewing and the postprocessing of dynamic data sets. Visual and semiquantitative analyses of MR images were performed by two radiologists in consensus (with 1 year and 11 years of experience in radiological breast imaging). First, LNs were detected by a synchronous viewing of the native T1w images as well as subtracted and nonsubtracted contrast-enhanced T1w images. Additionally, the STIR sequence was used as a kind of search tool. Then, LNs were categorized concerning their morphology and visual contrast behavior as shown in Table 2 and Fig. 1. If a type 4 LN with absent fat ratio was detected, the LN was further categorized by native T1w images if fatty parts are present or not. The number of each type of LN was registered, and the long- and short-axis diameter of the largest LN of each type (according the short axis) was measured. Afterwards, a region of interest (ROI) of at least 0.1 cm 2 was positioned in each type 4 LN on dynamic T1w images (without subtraction), and time-vs.-signal intensity curves were prepared (Fig. 2). The ROIs were placed inside the cortex (i.e., contrast-enhanced parts) of the LNs without covering parts of the fat hilum, if present. Cine mode was used to assure that the ROIs were contained within the same region of the LN on all dynamic series. According to previous studies, the prepared time-vs.-signal intensity curves were classified as type I–III: straight or curved lines (type I), an initial increase with a plateau afterwards (type II), and a washout curve with decreasing signal intensity after the initial upstroke (type III) [3]. If different LNs have been assessed by ROI analysis, the curve type with the highest classification was chosen for further evaluation. In case of consistent curve configuration, the curve with the highest peak of enhancement was chosen.

Table 1 Patients' characteristics (n=71) Age median in years (range) Reason for dynamic breast MRI High risk a Additional assessment b Median follow-up time after dynamic breast MRI in years (range) Kind of follow-up Clinical Clinical and radiological c a b c

50 (26–76) 23 (32%) 48 (68%) 1.2 (0.5-5)

Table 2 Scoring system for categorization of axillary LNs due to morphology and contrast behavior Type 1 Type 2 Type 3

11 (15%) 60 (85%)

According to the recommendations of the American Cancer Society [11]. Of unclear mammographic, sonographic and clinical findings. Mammography, breast ultrasound or dynamic breast MRI.

Type 4

LNs ≤0.5 cm in the short axis LNs N0.5 cm with a smooth contrast-enhanced rim and predominant fatty parts LNs N0.5 cm with predominant contrast-enhancing parts (minor or absent fatty parts). Enhancement is lower or equal compared to that of pectoralis muscle. LNs N0.5 cm with predominant contrast-enhancing parts (minor or absent fatty parts). Enhancement is stronger compared to that of pectoralis muscle.

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Fig. 1. Different types of LNs according to our scoring system on T1w postcontrast subtracted images. (A) Type 2 LN with predominant fatty parts and a smooth contrast-enhanced rim. (B) Type 3 LN with a predominant contrast-enhanced part; enhancement is lower or equal compared to the pectoral muscle. (C) Type 4 LN with a predominant contrast-enhanced part; enhancement is stronger compared to the pectoral muscle. (D) Another type 4 LN with predominant homogeneous enhancement without any signs of fat ratio. PM=pectoral muscle; arrow on the LN.

3. Results A detailed description of the detected LNs in accordance with our categorization is shown in Table 3. An overall number of 37 LNs categorized as type 4 (i.e., predominant and strong contrast enhancement) was detected in 29 women (41%). In 11 of these LNs, the entire LN was contrast enhanced and any fatty hilum was seen. In seven of these LNs, the fatty hilum was even missed in T1w native images. The mean long-axis diameter of all type 2–4 LNs was 1.5 (±0.6) cm, and the mean short-axis diameter was 0.8 (±0.2) cm. The mean long- to short-axis ratio was 1.9. The diameters of the different LN types are shown in Table 3. The dynamic evaluation of contrast enhancement in 29 women yielded the following findings: a type II curve was reached in 10 (34%) cases, and a type III curve was reached in 19 (66%) cases. None of the type 4 characterized LNs showed a type I curve with a steady signal increase in ROI analysis. The mean increase of signal intensity was 197% (±58%). If all data from the quantitative ROI analyses are summed up, a type II curve with an initial signal increase and a steady plateau (less than 10% decrease of signal enhancement) afterwards could be generated (Fig. 3). 4. Discussion Dynamic contrast-enhanced MRI of the breast is one of the most established and standardized imaging methods of the breast. Recent data could show that contrast enhancing breast lesions with a time-vs.-signal intensity curve that shows an initial rapid signal intensity increase and a washout (type II) or plateau (type III) afterwards are suspect for malignancy. Kuhl et al. found a sensitivity of 91% and specificity of 83% if types II and III were used as criteria to diagnose breast cancer. Schnall et al. described that 76% of curves that showed a washout pattern were

associated with cancer, and Bluemke et al. reported a sensitivity of only 21%, but a specificity of 90% using a washout enhancement pattern [3,12–15]. The signal intensity increase itself depends on the method used. Using widespread dynamic breast MRI standards (1.5 T; 0.1 mmol/kg Gd-DTPA), a signal intensity increase is supposed to be rapid when the increase exceeds 100% in the first 3 min after contrast medium application [4]. Kuhl et al. [3] defined a signal increase ≥80% within the first series as a rapid one; for Gribbestad et al., it was a signal increase ≥70% [16]. The definition of Fischer et al. [4] is the most established one at present, and there are less data concerning signal intensity increase using alternative methods (i.e., varying contrast medium dose or field strength). In the visual assessment of our study 41% of the healthy woman had axillary LNs with a predominant and strong contrast enhancement (type 4 LN according to our scoring system). In the assessment of the enhancement kinetics, these LNs showed either a type II (34%) or a type III (66%) curve. The mean signal intensity increase was 197% (±58%). Although we used a double contrast medium dose in our study, we define this as a rapid signal increase. Marklund et al. [17] described that the level of signal increase using the contrast medium dose twice is relatively 65% higher than using the single dose. Applying this to our study, the theoretical mean signal increase after single dose application might be approximately 120%. Thus, 41% of the examined healthy women did show strong contrast-enhancing LNs with suspicious dynamic curve configuration (i.e., type II or type III). However, the reason for this remains unclear. To our knowledge, this cannot yet be explained by physiological phenomena. A reason might be an unspecific lymphadenitis due to viral, drug, or inflammatory affection. Modifications of the LN structure like edema, hyperemia, and infiltration of LN sinuses and stroma with polymorphonuclear

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Signal intensity

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Phase Fig. 2. T1w nonsubtracted image of two type 4 LNs (arrow), one without any fat ratio (A) and one with a remaining fat hilum (B). ROI positioned in the cortex of the node, not covering the hilum, if present. The corresponding time-vs.-signal intensity curves show a rapid signal increase—one with a following washout effect (A) and the other (B) with a plateau. Technical note: Phase interval is 50 s.

leukocytes are noted in response to various inflammatory and infectious disorders. These can lead to follicular and interfollicular hyperplasia or sinus histiocytosis [18,19]. It could be assumed that these common changes are associated with changes in blood perfusion. Some case reports even pointed out that inflammatory intramammary LNs might be a potential pitfall in dynamic breast MRI. [20,21].

There are two publications concerning the enhancement kinetics of axillary LNs of patients with breast cancer. Kvistad et al. pointed out that the curve configuration of axillary LNs on dynamic breast MRI (1.5 T, single dose) is a nonspecific criterion to evaluate metastatic affection [9]. Patients with breast cancer did show axillary LNs with time-vs.-signal intensity curves with a washout effect whether they had LN metastases or not, although the

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Table 3 Categorization and distribution of axillary LNs due to morphology and contrast behavior as well as related diameters

No LN Type 1 Type 2 Type 3 Type 4 Types 2–4

Patient based (n=71)

LN based (n=313)

Long-axis diameter (mean, S.D.)

Short-axis diameter (mean, S.D.)

Long- to short-axis ratio

5 (7%) 55 (77%) 28 (39%) 23 (32%) 29 (41%) 51 (72%)

187 (60%) 50 (16%) 39 (12%) 37 (12%) 126 (30%)

1.9 (0.8) 1.4 (0.4) 1.2 (0.4) 1.5 (0.6)

≤0.5 0.9 (0.2) 0.8 (0.2) 0.8 (0.1) 0.8 (0.2)

2.0 1.8 1.6 1.8

mean initial signal intensity increase was significantly higher when patients had a positive nodal status in comparison to the negative ones (152% vs. 61%). According to our argumentation, the initial signal intensity increase of 61% in patients with a negative nodal status seems quite low. In contrast to Kvistad et al., Murray et al. [8] described a strong overlap in the initial signal increase in patients with positive and negative nodal status. However, a bias of the results due to a missing 1:1 correlation of the findings on dynamic breast MRI and histopathology has to be considered in both studies. Unfortunately, it is nearly impossible to implement a study with a 1:1 correlation, and this points out the necessity of analyzing the characteristics of axillary LNs of healthy women as first done in our study. Our study points out that contrast enhancement and the enhancement kinetics are not reliable criteria to evaluate the dignity of apparent axillary LNs. Consequently, additional morphologic criteria such as size and shape have to be considered. Those criteria have already been investigated in numerous studies, which are mostly based on ultrasound [7]. Our study is in line with other publications that point out an oval shape (long- to short-axis ratio ≥1.5) [22] and the existence of a fat ratio as criteria for a negative nodal status. As the detection of a fat ratio on ultrasound depends on the size of the LN itself, this criterion should be considered reliable only if the LN exceeds ≥1 cm [22]. Also, in

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Phase Fig. 3. Mean time-vs.-signal intensity curve±S.D. of all 29 assessed ROI analyses of type 4 LNs. The curve shows a maximum initial signal increase up to 184% with a following steady plateau according to a type II curve. Technical note: Phase interval is 50 s.

our study, some LNs showed no signs of any fat ratio on breast MRI at all. This might also be due to the rather small size of the LNs in our sample. Overall, in our study, the mean long-axis diameter (LN type 2–4) was 1.5 cm, and the mean short-axis diameter was 0.8 cm. Especially concerning type 4 LNs, the mean longaxis diameter was 1.2 cm, and the mean short-axis diameter 0.8 cm. Referring to present literature [7], the size of the LN itself could hardly be considered as a definite and reliable criterion for the dignity of LNs. Nevertheless, some studies declare an LN as metastatic just because of a largest diameter ≥1 cm [23] or a short-axis diameter ≥0.5 cm [24]. Under these conditions, positive predictive values of 89% (no prevalence data published) and 91% (prevalence of 7%) have been reached. With due consideration to our results, these findings are difficult to comprehend. Mumtaz et al. [25] set an intense STIR signal (compared to the soft tissue) as indicator for malignancy. Even if the STIR signal was not the focus of our study, we used the STIR as a kind of search sequence, and we noted that most LNs showed a visually increased STIR signal compared to the soft tissue. To assess this might be the focus of additional future studies. This, however, is problematic since the STIR signal cannot be further graduated quantitatively or semiquantitatively without a standardized saline phantom within the field of view [26]. Another approach in axillary LN assessment might be found in diffusion weighted sequences, which are in general increasingly applied in MRI. Some limitations of our study have to be considered. The used standard breast coil was not especially centered on the axillary region, as we aimed not to evaluate the whole axillary region but those LNs which are routinely detected by a standard breast coil. In all cases, except for four (which were excluded), we found a sufficient image quality of the covered axillary region. Sometimes, we found aliasing artifacts. However, we did not consider them as significant limitation as long as they appeared in all dynamic series in the same way. Women with a known history of malignant or systemic inflammatory diseases were excluded. However, we cannot exclude that some women had a mild systemic infection, such as a common cold, which was not registered in the clinical report. Those infections might affect the size, morphology, and contrast behavior of axillary LNs. Nevertheless, those

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common circumstances have to be considered in women undergoing breast cancer staging as well. 5. Conclusion A high number of healthy women have axillary LNs with a predominant and strong contrast enhancement and suspicious enhancement kinetics on dynamic breast MRI. The previous understanding of enhancement kinetics of breast lesions cannot be applied to the axillary LNs. Whenever the radiologist makes a statement on LNs apparent on preoperative dynamic breast cancer, he should be aware of these facts to avoid confusion or even falsepositive assessment. Morphological aspects of the LN, i.e., synopsis of size, shape, and fat ratio, should be considered primarily, unless metabolic imaging such as positron emission tomography–computed tomography is used. Evaluation of morphological features is still a domain of ultrasound, which also secures a documentation of the whole axilla as well as the paraclavicular region. References [1] Heywang-Köbrunner S. Contrast-enhanced magnetic resonance imaging of the breast. Invest Radiol 1994;29(1):94–104. [2] Kuhl CK, Bieling H, Gieseke J, Ebel T, Mielcarek P, Far F, Folkers P, Elevelt A, Schild HH. Breast neoplasms: T2⁎ susceptibility-contrast, first-pass perfusion MR imaging. Radiology 1997;202(1):87–95. [3] Kuhl CK, Mielcareck P, Klaschik S, Leutner C, Wardelmann E, Gieseke J, Schild HH. Dynamic breast MR imaging: are signal intensity time course data useful for differential diagnosis of enhancing lesions? Radiology 1999;211(1):101–10. [4] Fischer U, Kopka L, Grabbe E. Breast carcinoma: effect of preoperative contrast-enhanced MR imaging on the therapeutic approach. Radiology 1999;213(3):881–8. [5] Macura KJ, Ouwerkerk R, Jacobs MA, Bluemke DA. Patterns of enhancement on breast MR images: interpretation and imaging pitfalls. Radiographics 2006;26(6):1719–34 [quiz 1719]. [6] Erguvan-Dogan B, Whitman GJ, Kushwaha AC, Phelps MJ, Dempsey PJ. BI-RADSMRI: a primer. AJR Am J Roentgenol 2006;187(2): W152–60. [7] Wasser K, Schnitzer A, Brade J, Schoenberg SO. Non-invasive imaging modalities for preoperative axillary lymph node staging in patients with breast cancer. Radiologe 2011;50(11):1022–9. [8] Murray AD, Staff RT, Redpath TW, Gilbert FJ, Ah-See AK, Brookes JA, Miller ID, Payne S. Dynamic contrast enhanced MRI of the axilla in women with breast cancer: comparison with pathology of excised nodes. Br J Radiol 2002;75(891):220–8. [9] Kvistad KA, Rydland J, Smethurst HB, Lundgren S, Fjosne HE, Haraldseth O. Axillary lymph node metastases in breast cancer: preoperative detection with dynamic contrast-enhanced MRI. Eur Radiol 2000;10(9):1464–71.

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