Breast dynamic contrast enhanced MRI: fibrocystic changes presenting as a non-mass enhancement mimicking malignancy

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, in situ ductal carcinoma (DCIS), invasive lobular carcinoma and some cases of oestrogen receptor-negative invasive ductal carcinoma. The mass enhancement is usually confined to malignant or benign tumors.8-11

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.

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 et al. reported two studies with 31 patients and 11 patients, analysing FCCs in DCE-MRI examination and MR spectroscopy for choline detection.^19,20 Van den Bosch et al. and Kiyak et al. reported morphological and kinetic features of FCCs on DCE-MRI in the group of 14 patients and 27 patients, respectively.^21,22

Our study included 46 symptomatic patients with pathologically confirmed FCCs presenting as NME, mimicking malignancy in DCE-MRI examination. Chen et al. reported that FCCs on DCE-MRI had characteristics of NME in 39% of cases, mass enhancement in 35% of cases, while 26% of cases were non-enhancing lesions.19 According to the published data, breast DCE-MRI has the potential to distinguish benign from malignant mass lesions effectively. Nevertheless, DCE-MRI is inferior in discriminating benign from malignant NME lesions.23 Hence, a meticulous analysis of the multiple, standardized parameters from BI-RADS lexicon is crucial to achieve a higher diagnostic performance of DCE-MRI in the case of FCCs presenting as NME, including the distribution of enhancement, the internal enhancement pattern, the type of TICs, the wash-in, and the signal intensity on T2W images.

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 et al. emphasize that „the more extensive distribution of enhancement is, the less suspicious for malignancy it is”.8Agrawal et al. showed that the diffuse enhancement was highly suggestive of benign lesions.24 On the other hand, segmental NME was considered the most suspicious, with the positive predictive value (PPV) for malignancy from 76% to 100%, confirmed with the study by Tozaki and Fukuda.25Our results show that FCCs mainly show the more extensive distribution - regional and diffuse, suggesting benign aetiology of the condition.

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 et al., Tozaki and Fukuda),when the enhancement is heterogeneous or clumped the risk of malignancy is considered high, with the PPV of 53-58%, while the homogenous enhancement has low PPV for malignancy, up to 5%.The stippled enhancement represents the normal breast parenchymal enhancement.8,25 Since almost 80% of the cases in our study showed heterogeneous or clumped enhancement on DCE-MRI, the internal pattern can be one of the most important reasons for mimicry of the breast cancer by FCCs.

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 et al. 90% of NME lesions had the type 1curve.19 Bartella et al. reported predominantly the type 2 curve in cases of malignant NME.27 Goto et al. did not find any differences in the kinetic curve enhancement between benign and malignant NME lesions.28 These differences may be partly due to the fact that the time-intensity curves are based on the semiquantitative analysis of gadolinium contrast uptake with the free-hand selected region of interest (ROI) on the heterogeneous areas of NME. Some recent studies suggested that the quantitative analysis using automated computer-aided diagnosis (CAD) can overcome subjectivity of the free-hand selection of ROI.29 The postcontrast enhancement rate types in our study were slow in 15patients (32.6%), moderate in 14 patients (30.4%)and fast in 17 patients (37.0%). Based on the published data, slow wash-in indicates benign lesions, medium wash-in may indicate lesions like mastitis, fresh scar, FCCs or DCIS, while the fast initial enhancement is suggestive of malignancy, especially when combined with the type 2 or the type 3 enhancement curve.30

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 et al. published in 2015, which anticipated a potentially important role of DCE-MRI in case of a typical hyperplasia.31 Hartman et al. showed that in women with atypical hyperplasia a lifetime risk of breast cancer approaches 30% at 25 years. This high cumulative incidence is not widely recognized, and thus screening DCE-MRI is not routinely recommended for these patients.13,32 Hartman et al. suggested more intensive screening of women with atypical hyperplasia, with DCE-MRI added to mammography, as well as the use of selective oestrogen-receptor modulators and aromatase inhibitors to prevent breast cancer in women with a typical hyperplasia. We hypothesized that the differentiation of atypical hyperplasia by DCE-MRI examination from other types of FCCs could be helpful in DCE-MRI screening. Our study was limited by the low number of proliferative lesions with atypia, thus necessitating further investigation.

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