Fig. 1
32-year-old asymptomatic female with a known pathologic BRCA1 mutation attending high-risk multimodal screening. MRI performed during oral contraceptive use (a) shows very strong bilateral background parenchymal enhancement, limiting the diagnostic capabilities of MRI. On a short-term follow-up exam 6 months later after discontinuation of oral contraceptive use (b), the background parenchymal enhancement has almost completely subsided
For screening high-risk women, a standard contrast-enhanced dynamic imaging protocol at 1.5 or 3 T with a scan duration of at least 5 min post contrast and a good compromise between spatial resolution (<1 × 1 mm in-plane) and speed (e.g. around 1 min or less per series) should be used. Typically a T1-weighted, in-phase, 3D gradient echo sequence with or without fat saturation is used for the dynamic scanning. The addition of a high-resolution, preferably not fat-saturated, T2-weighted sequence may improve specificity and facilitate correlation with the other imaging modalities, especially ultrasound. To maximize sensitivity and specificity in high-risk patients, abbreviated protocols should be avoided in this situation.
Sufficient time resolution not only improves specificity but is also important to increase sensitivity by providing a better separation between the usually more rapid enhancement of malignant lesions and the slower parenchymal background enhancement.
The most important predictors of malignancy in enhancing mass lesions on MRI are irregular or spiculated margins (regardless of type of enhancement curve) as well as strong and fast enhancement in the inital phase (even in lesions with a relatively circumscribed margin), especially when combined with later washout or rim enhancement. Further clues regarding the type of lesion may be obtained from the T2-weighted images (e.g. fatty hilum in intramammary lymph nodes and lobular composition with predominantly high signal intensity on T2-weigthed images in fibroadenomas). With a combination of these morphological and contrast-enhancement criteria most enhancing mass lesions with a size of more than 5 mm can usually be characterized reliably on MRI. It is important to realize however, that morphological criteria are less reliable in smaller lesions due to the limited spatial resolution of MRI. This is especially true for lesions 5 mm or less in size. Obviously this cutoff will vary somewhat with the spatial resolution of the employed imaging sequence. In order to avoid a delay in diagnosis, small enhancing masses on MRI which are clearly new or increased in size compared to the prior exam usually will require histological confirmation through biopsy, even if no corresponding correlate is found on mammography or second-look ultrasound. This is especially true for BRCA1 mutation carriers, in whom an otherwise non-descript small enhancing mass lesion may represent an aggressive triple-negative breast cancer.
Characterization of non-mass enhancement on MRI is much more difficult, since the overlap of malignant lesions with physiological and benign changes in the breast is much bigger. In this situation careful second-look correlation with clinical exam, ultrasound and mammography (presence of microcalcifications?) is important to improve the specificity of MRI, since a non-mass enhancement on MRI with a correlating finding on another modality, even if the correlating finding by itself is considered non-specific, will have a higher probability of malignancy [15] (Fig. 2). If no correlating finding is found for a non-mass enhancement on MRI, short-term follow-up may be considered instead of immediate MRI-guided biopsy. If the non-mass enhancement persists (or even increases in size) on short-term follow-up, MRI-guided biopsy is usually indicated.
Fig. 2
49-year-old asymptomatic female with a known pathologic BRCA2 mutation attending high-risk multimodal screening. MRI shows a small area of non-mass enhancement with linear distribution in the left breast (a, b), which was not present on the prior exam a year ago. In the initial phase after contrast administration the lesion has a “clumped” internal enhancement pattern consisting of several small enhancing foci closely grouped together, best seen on the MIP-projection at 2 min after contrast injection (a). The enhancement persists in the delayed phase (b) and becomes increasingly confluent over time. On digital mammography (c), a corresponding subtle cluster of four or five, predominantly round calcifications is seen, which in itself probably would not have warranted biopsy. Due to the combination of non-mass enhancement on MRI and the presence of corresponding calcifications, a stereotactic vacuum-assisted biopsy (d) was performed, which confirmed a 6-mm DCIS intermediate-grade. Because of her BRCA2 carrier status, the patient opted for a bilateral subcutaneous mastectomy, which showed only a small amount of residual DCIS in the left breast in the immediate vicinity of the biopsy cavity
Despite the fact, that contrast-enhanced MRI is usually considered a very safe procedure [16], appropriate safeguards (e.g. single-dose protocols, use of low NSF-risk contrast media and screening for renal function impairment) should be put in place considering the repeated nature of the exam in screening. This has become even more important after the recent reports of Gadolinium depositions in the brain after repeated contrast-enhanced MRI’s.
In some patients, MRI cannot be performed e.g. due to prior adverse reactions to contrast media, severe claustrophobia or implanted medical devices incompatible with MRI. In these patients mammography will need to play a bigger role and may have to be started earlier (e.g. from age 30). Alternatively, at least in the case of BRCA1/2 mutation carriers, risk-reducing surgeries may have to be considered.
Mammography
The role of mammography in high-risk screening is substantially different from its role in population-based mammography screening, where it represents the primary screening modality. In high-risk multi-modality screening, mammography becomes an adjunct to MRI. Its importance increases in situations, where MRI is more difficult to evaluate, e.g. in cases with very strong background parenchymal enhancement. If a high-quality MRI with little or no background parenchymal enhancement is available, the primary task of mammography is to detect microcalcifications, which cannot be detected on MRI at all, and subtle architectural distortions, which are often better depicted on mammography due to its higher spatial resolution. With this a small amount of additional cancers (usually in-situ or low-grade invasive cancers) can be found in addition to MRI. This effect will be larger in BRCA2 mutation carriers than in BRCA1 mutation carriers, since cancers associated with microcalcifications are less common in BRCA1 mutation carriers [17].
Whenever possible, digital mammography should be used in high-risk screening [5], due to its higher sensitivity in young premenopausal women [18] as well the superior depiction of microcalcifications, the key feature of cancers detected solely by mammography in multimodality high-risk screening.
In younger women, especially in BRCA1 and BRCA2 carriers who may have a higher risk for radiation injury [19], bilateral MLO-views only and/or mammography only every 2 years may be considered. In cases with abnormal findings on MRI, mammography becomes an important second-look tool with additional tailored views as well as the option to perform digital breast tomosynthesis, which due to its cross-sectional nature can more easily be correlated with MRI. In many cases a mammographic correlate for the MRI finding can be found and if necessary biopsy can be performed under stereotactic guidance.
Ultrasound
The likelihood that a breast ultrasound performed after a normal MRI exam will detect additional cancers occult on MRI is very small [5, 20]. One of the main tasks of the ultrasound in high-risk multimodality screening is to further work-up and correlate non-specific findings on MRI. In many cases, ultrasound is able to identify typical small lymph nodes or fibroadenomas as explanation for a small enhancing lesion on MRI, thus increasing the specificity of MRI [21]. Most solid enhancing mass lesions on MRI larger than 5 mm (benign or malignant) will have some correlate on tailored ultrasound imaging and if necessary ultrasound-guided biopsy can easily be performed under ultrasound-guidance. With small lesions biopsied under ultrasound guidance, a marker clip should be placed to allow for correlation with a follow-up MRI in cases with inconclusive correlation between imaging findings and biopsy results.
Due to the virtual absence of side-effects or contraindications, ultrasound is the modality of choice for an additional 6-month interval exam in BRCA1/2 carriers as well as during pregnancy and lactation, as both MRI and mammography are contraindicated during pregnancy and often severely limited during lactation.
Specific Imaging Findings in High-Risk Patients
The underlying genetic abnormalities in high-risk women not only determine the age and frequency, with which breast cancer will occur, but also influence the histological type and imaging presentation of breast cancers [22, 23]. Knowledge of the genetic status of a particular patient is therefore important for choosing the optimal imaging strategy in an individual high-risk patient. Around 69% of all invasive cancers found in BRCA1 mutation carriers are triple-negative, compared to around 16% in BRCA2 mutation carriers [22]. BRCA1-associated triple-negative cancers are particularly fast growing and often lack typical imaging features of sporadic breast cancers, such as irregular margins or spiculation, and microcalcifications are rare in these types of tumors. These tumors are therefore often occult on mammography [24–27] and may be misinterpreted as cysts or fibroadenomas on ultrasound due to the lack of posterior acoustic shadowing and relatively circumscribed margins [28, 29]. On MRI, triple-negative breast cancers are usually easy to recognize despite the relatively benign morphological appearance due to their very strong and fast initial contrast uptake, often combined with rim enhancement in larger lesions [30] (Fig. 3). Imaging findings in BRCA2-associated breast cancers are usually more similar to sporadic breast cancers and microcalcifications-associated in-situ cancers are more common in BRCA2 than in BRCA1 mutation carriers [23].
