Fibrocystic changes (FCCs) are the most frequent benign conditions of breast, diagnosed in 50% of women examined clinically and in 90% of women in histopathological studies. These benign disorders have two important implications from the point of view of breast cancer diagnosis and management. First, FCCs can mimic breast cancer on clinical examination, mammography and breast ultrasonography, leading to unnecessary breast biopsies and patient anxiety. Second, some types of FCCs represent a risk factor for the subsequent development of breast cancer.1 Based on a classification system of FCCs proposed by Dupont and Page and according to other studies, women with histologically confirmed nonproliferative lesions have no increased breast cancer risk. On the contrary, women whose breast biopsies show proliferative lesions with or without atypia are at risk of developing cancer, with relative risk ranging from 3.9-13.0 and 1.3-1.9 respectively.2-4
Combining morphological and enhancement kinetics features of the breast lesions, dynamic contrast-enhanced MRI (DCE-MRI) shows the highest sensitivity of all imaging methods in detecting breast diseases, up to 100%. Nevertheless, the specificity in the differentiation between benign and malignant lesions is lower, up to 75%.5 The major cause of false positive findings in DCE-MRI examination and consecutive unnecessary biopsies are the lesions with non-mass enhancement (NME). NME refers to the lesion that is seen only on post-contrast DCE-MRI sequences and does not have space-occupying effect. The enhancement pattern of NME is distinct from normal surrounding breast parenchyma and may contain interspersed fat. On the contrary, a mass enhancement is a three-dimensional space occupying lesion.6,7 The causes of NME include FCCs, inflammatory benign lesions,
Our study of pathologically confirmed FCCs presenting as NME in DCE-MRI examination has two goals: 1) to analyse morphological and enhancement kinetics features of FCCs, 2) to compare these features between nonproliferative lesions, proliferative lesions without atypia and proliferative lesions with atypia.
In the period of two years (January 2010 to January 2012) a total of 947 patients were examined by two radiologists (MZC and NMM) using the standardized breast DCE-MRI full diagnostic protocol. From this group, 46 patients with FCCs presenting as NME were selected and retrospectively reviewed. The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board Committee (No.4502-01/2011). All patients gave written informed consent to participate in DCE-MRI examination. The age of the patients was 50.78 ± 8.99 years. In all premenopausal women DCE-MRI was performed in the second and third week of the menstrual cycles. None of the patients had previous breast biopsy, breast surgery or current hormone replacement therapy. All patients initially had unilateral breast lesion suspicious of malignancy either on clinical examination, mammography or ultrasonography. The lesions were presented as calcifications or asymmetric tissue on mammography and hypo-echoic non-mass lesions on ultrasonography (BI-RADS 4a to BI-RADS 4c categories according to the ACR BI-RADS lexicon).6,12 The indication for breast DCE-MRI prior to biopsy was to evaluate the local extent of the lesion in the dense breast on mammography (32 patients) or suspected multifocal lesions on mammography and/or ultrasonography(14 patients).13 After the pathological confirmation of FCCs, the patients were examined biannually by physical examination and mammography. During the predefined follow-up period, no ipsilateral or contralateral breast cancer was detected.
The DCE-MRI examinations were performed with a 1.5 Tesla MRI unit (Magnetom Avanto, Siemens Medical Solutions, Erlangen, Germany) with dedicated bilateral breast coil and the patient in the prone position. The standard protocol was used for the axial-plane images with the slice thickness of 2 mm Table 1.14 The contrast medium was gadopentetate dimeglumine (Magnevist, Bayer Schering Pharma, Berlin, Germany) applied as the bolus injection of 0.1 mmol/kg body weight injected with the automatic injector (Mississippi, Ulrich Medical, Ulm, Germany) at the rate of 2 mL/s, followed by the flush of 20 mL saline. Contrast-enhanced dynamic sequences were acquired five times every 1 min 23s. The post processing methods, including a creation of time intensity curves (TICs),
Standard dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) protocol for axial-plane images for T1-weighted FLASH 3D precontrast and five postcontrast series 3D = three-dimensional; DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; FLASH = fast low-angle shot pulse sequence; TIRM = turbo inversion recovery magnitude; TSE = turbo spin-echoT2- T2- T1- T1- weighted weighted weighted weighted MRI sequence/ parameters TIRM TSE TSE FLASH 3D Echo time (ms) 60 70 12 4.8 Repetition time (ms) 7690 5900 910 9.1 Inversion time (ms) 180 Flip angle (°) 150 180 90 25 Field of view (mm×mm) 340×340 340×340 340×340 340×340 Image matrix 320×256 384×319 320×234 576×564
Two experienced radiologists in breast MRI,ZCM, 20 yr. and MMN, 7 yr., reviewed the DCE-MRI examinations. Based on the fifth edition of the BI-RADS lexicon, published in 2013, the following morphokinetic features of NME were analysed: distribution of enhancement (focal, linear, segmental, regional, multiple regions, diffuse), internal enhancement pattern (homogeneous, heterogeneous, clumped, clustered ring enhancement, stippled), type of TICs (persistent curve or type 1, plateau curve or type 2, wash out curve or type 3), wash-in
A surgical biopsy was performed in all patients. Among them, 21 patients with nonpalable lesions, prior to the biopsy underwent a radioguided occult lesion localization (ROLL) procedure with Technetium-99m, under stereotactic or ultrasonographic guidance.15 Haematoxylin and eosin stained slides of formalin-fixed and paraffin-embedded tissue blocks were assessed by a pathologist, experienced in breast pathology. According to the classification system of Dupont and Page, the lesions were classified as nonproliferative lesions, proliferative lesions without atypia, and proliferative lesions with atypia (atypical ductal and lobular hyperplasia).2
Following DCE-MRI features of NME were analysed: distribution of postcontrast enhancement, internal enhancement pattern, type of TICs, wash-in, and signal intensity on T2W images. These distinctive DCE-MRI features of NME were compared for three groups of FCCs: nonproliferative lesions, proliferative lesions without atypia, and proliferative lesions with atypia. Frequencies were used to describe the distribution of categorical variables. The difference between investigated variables in three groups of FCCs was analysed using χ2 test. P values less than 0.05 were considered statistically significant. SPSS for Windows, Statistics version 16.0. (SPSS Inc., Chicago, USA) was used to perform statistical analyses.
The lesions were detected clinically in 25 patients(54.3%), on mammography in 43 patients (93.5%)and by breast ultrasonography in 30 patients(65.2%).
Out of 46 biopsies, nonproliferative lesions were found in 11 patients (24%), proliferative lesions without atypia in 29 patients (63%) and proliferative lesions with atypia in six patients (13%). On DCE-MRI examination, all cases were presented as unilateral non-mass enhancement of BI-RADS 4category (Figure 1)
Forty-three lesions (93.5%) were equal to or larger than 1 cm in size and three lesions were smaller than 1 cm and larger than 0.5 cm in size (6.5%). The distribution of the postcontrast enhancement was segmental in 11 patients (23.9%) and regional or diffuse in 35 patients (76.1%). The other types of distribution (focal, linear enhancement and multiple regions) were not found. The internal enhancement pattern was homogeneous in two patients(4.3%), heterogeneous and clumped in 36 patients(78.3%), and stippled in eight patients (17.4%).Clustered ring enhancement was not detected. The types of time-intensity curves were persistent(type 1) in 17 patients (37.0%), plateau (type 2) in 25 patients (54.3%), and wash out (type 3) in four patients (8.7%). The initial postcontrast signal intensity enhancement (enhancement rate, wash-in)was slow in 15 patients (32.6%), moderate in 14 patients (30.4%), and fast in 17 patients (37.0%). On T2W images FCCs were associated with clustered microcysts in 25 cases (54.3%).
Nonproliferative lesion, proliferative lesions without atypia and proliferative lesions with atypia: dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) morphological and enhancement kinetics features, based on BI-RADS lexicon
Statistical difference | Proliferative lesions without atypia (N = 6) | Proliferative lesions with atypia (N = 29) | Non proliferative lesions (N = 11) | The DCE-MRI features of fibrocystic change | |
---|---|---|---|---|---|
p = 0.454 | 1 | 1 | 1 | 0.5 < d < 1 cm | Size |
5 | 28 | 10 | d ≥ 1cm | ||
p = 0.168 | 3 | 7 | 1 | Segmental | NME distribution |
3 | 22 | 10 | Regional or diffuse | ||
p = 0.722 | 0 | 2 | 0 | Homogeneous | NME internal |
1 | 4 | 3 | Stippled | ||
5 | 23 | 8 | Heterogeneous or | ||
p = 0.097 | 3 | 8 | 6 | Persistent | TIC |
3 | 19 | 3 | Plateau | ||
0 | 2 | 2 | Wash out | ||
p = 0.752 | 2 | 8 | 5 | Slow | Wash-in |
1 | 10 | 3 | Moderate | ||
3 | 11 | 3 | Fast | ||
p = 0.014 | 1 | 18 | 2 | Present | Microcysts (T2W |
5 | 11 | 9 | Absent |
d = longest diameter; DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging; NME = non-mass enhancement; TIC = time-intensity curve; T2W = T2-weighted
As shown in Table 2, the features of nonproliferative lesions, proliferative lesions without atypia and proliferative lesions with atypia on DCE-MRI examination did not show statistically significant difference in the term of the size (p = 0.454), the distribution of postcontrast enhancement (p = 0.168),the internal enhancement pattern (p = 0.722), the types of time-intensity curves (p = 0.097) and the initial postcontrast signal intensity enhancement (p= 0.752). Presence of microcysts on T2W images in these three groups of FCCs was statistically significant compared to the lack of the feature (p = 0.014).
Numerous studies have demonstrated the clinical importance of FCCs, related to the high prevalence of the condition, the considerable impact on quality of life and the increased breast cancer risk for women with proliferative lesions.2-4,16-18
Nevertheless, only few studies analysed features of FCCs on DCE-MRI, based on the limited number of cases. Chen
Our study included 46 symptomatic patients with pathologically confirmed FCCs presenting as NME, mimicking malignancy in DCE-MRI examination. Chen
In our study the postcontrast enhancement of FCCs was unilateral in all patients. The most frequent types of the distribution of NME were regional - involving more than 25% of a breast quad-rant, and diffuse - involving the entire breast (35patients or 76.1%). Segmental distribution, reflecting the ductal distribution, was detected in 11 patients (23.9%). Thomassin-Naggara
The internal pattern of enhancement in our study was heterogeneous and clumped in 36 cases(78.3%). The stippled enhancement was noted in eight patients (17.4%) and homogeneous in two patients (4.3%). According to the previous studies(Thomassin-Naggara
Kinetic curve enhancement reflects functional aspects of blood vessel permeability in normal and pathological breast tissue after intravenous gadolinium contrast application. According to the published data, the permanent enhancement (type1 time-intensity curve) is seen in benign lesions in85% of cases, the plateau (type 2) curve is seen in 36% of malignant cases and the washout (type 3)curve in 57% of malignant cases.26 In our study the majority of patients have type 2 curve (25 or 54.3%),followed by type 1 curve in 17 patients (37%) and type 3 in four patients (8.7%). Generally, the published data about the kinetic curve enhancement of NME significantly differ. In the study of FCCs by Chen
NME lesions in our study of FCCs were associated with microcysts on T2W images in 54.3% ofcases, which was suggestive of benign conditions.8
Additionally, we investigated DCE-MRI morphokinetic features of three distinct histological types of FCCs: nonproliferative lesions (11 cases or24%), proliferative lesions without atypia (29 casesor 63%) and proliferative lesions with atypia (6 cases or 13%). Our results show that nonproliferative lesions, proliferative lesions without atypia and proliferative lesions with atypia have similar morphokinetic features (distribution of NME, internal pattern of enhancement, type of TICs and wash-in)with the exception of the significant association of microcysts with proliferative hyperplasia without atypia. To our knowledge, our study is the first, which analyses the morphokinetic features of distinct histological types of FCCs on MRI examination. Our study was prompted by the report from Hartman
Our study has some limitations. We did not analyse incidental findings of FCCs on DCE-MRI. Our analysis was conducted in the selected group of symptomatic patients: the lesions were suspicious of malignancy on clinical examination, mammography or ultrasonography and larger than 1 cm in DCE-MRI examination in 93.5% of cases. These facts may have influenced the interpretation and results of DCE-MRI examination.
In conclusion, the profile of FCCs presented as NME in DCE-MRI examination predominantly includes: unilateral regional or diffuse distribution(76.1% of cases), heterogeneous or clumped internal pattern of enhancement (78.3% of cases), plateau (type 2) time-intensity curve (54.3% of cases)with moderate or fast wash-in (67.4% of cases), and associated clustered microcysts (54.3% of cases). Although these findings do not have the classic appearance of malignancy, they are sufficiently suspicious to recommend the biopsy, as final BI-RADS 4 category. In case of NME, proliferative lesions without atypia are the most frequent type of FCCs (63%), followed by nonproliferative lesions(24%), and proliferative lesions with atypia (13%). DCE-MRI cannot show the subtle histological differences between nonproliferative lesions, proliferative lesions without atypia and proliferative lesions with atypia. According to some novel data, MR diffusion-weighted imaging (DWI), related to tissue cellularity and thermal motion of water molecules instead of permeability of blood vessels after the contrast uptake, may be more specific than DCE-MRI to define the benign nature of FCCs.33,34