Studies and quality analysis
We included 18 studies, but the highest number of studies that could be used to answer a specific endpoint was 8 (sensitivity and contralateral findings). Strong evidence is therefore lacking and this review is thus a clear call for more substantial research in this area. The overall study quality of all studies is, according to the QUADAS score, reasonably high (lowest score = 9/14). However, this tool does not include the study size in the analysis, which was generally low. The tool places a strong emphasis on the relation of the test to the reference standard (typical for observational studies). In all studies, the reference standard was pathology and therefore always acceptable as gold standard. However, the test results (in this case the MRI reports), were never shielded from the pathologist who performed the pathologic evaluation. In studies that were performed to evaluate the visual characteristics of ILC on MRI a thorough description of the pathological examination was, deservedly so, not included [
23,
30,
32,
33,
36,
38,
41]. These studies thus scored a little lower. There are some other drawbacks that must be considered and that are not included in the QUADAS score. Firstly, all but 2 of the included 18 studies were retrospective in nature, and secondly, the applied MRI protocols were largely heterogeneous (see Table
1). However, the presented data were extracted from studies that made use of the various standards in MRI of the breast of the last decade and therefore give a reasonable overview of the overall capability of MRI in ILC imaging in this period.
Sensitivity
The sensitivity of physical examination and conventional imaging for ILC of the breast is not optimal. The sensitivity of physical examination for ILC ranges between 65 and 98% [
10,
45‐
47], with usually over 50% of patients presenting with palpable abnormalities.
The sensitivity of mammography for ILC (BI-RADS 3 or higher) ranges between 81 and 92% in literature [
10,
45‐
51]. In a recent study that evaluated intra- and interobserver variability, sensitivity even ranged from 88 to 98% [
52], which could be regarded as sufficient. However, ILC often do not appear as a malignant lesion on mammography; approximately 30% is classified as equivocal and sensitivity is then approximately 57–59% [
51].
The overall sensitivity of mammography in the current analysis appears lower than findings in the literature on mammography in ILC. However, equivocal findings may have been classified as undetected lesions in some studies resulting in the overall lower results. Nevertheless, the sensitivities of only 34% found by Berg et al. [
40], and 50% found by Munot et al. [
28] are on the lower end of the spectrum. Munot et al. [
28] did not state which views constituted their mammograms, while Berg et al. [
40] made craniocaudal, mediolateral and spot-compression views on a standard mammography machine, which we regard as common practice. A possible explanation for the poor results in the study by Berg et al. [
40] may be that they defined an ILC as a focus of tumor, thereby allowing more tumors to be present in one breast, whereas other authors defined this as multifocal or multicentric tumors and thus as detected when at least one lesion was visible on mammography.
In literature, the reported sensitivity of ultrasound for ILC ranges between 68 and 98% [
47,
53‐
58]. As this range is comparable to the range found in the present evaluation, we are of the opinion that an overall sensitivity of 83% is accurate. However, application of newer high-frequency ultrasound transducers may improve sensitivity. Initial series using 7.5 MHz transducers show sensitivities of 68% [
47] and 78% [
56], whereas series that used 10–13 MHz transducers report sensitivities up to 98% [
57,
59].
Contrast-enhanced MRI is nowadays widely accepted as the most sensitive modality for detection of malignancy of the breast. Early reports on overall sensitivity of MRI for breast lesions range from 93 to 100% [
13,
60‐
63]. Thus, the sensitivity of MRI found for ILC in the studies presented herein and the overall sensitivity of 93.3% calculated from these studies are not different from those known for malignancy in the breast in general. The relatively low heterogeneity of all studies describing lesion detection as well as detection of additional lesions in the ipsi- and contralateral breast show that the applied MRI technique only has a minor impact on the ability of MRI to detect lesions.
The overall sensitivity could even be increased to 96% (95% CI 92–98%) if an early study is excluded from the analysis [
34]. This study reported a sensitivity for ILC of only 83%, a discrepancy that may well be explained by the fact that the slice thickness in this study was 4.2 mm, thicker than in any of the other presented studies, which could have had a negative impact on sensitivity. Moreover, 15 of 23 patients in their series were scanned with a FLASH 3D sequence with TR 8.4/TE 3.0, resulting in image acquisition with a phase-shift of water and fat, which might have further decreased their sensitivity, although this was not apparent from their data.
It must be taken into account that the acquired sensitivity in all studies was achieved in cases where prior knowledge of the existence of ILC was present. Mostly because of the retrospective nature of the presented studies, but also because the two prospective studies both included their patients on the basis of histological proof of invasive (lobular) carcinoma by core biopsy. It is therefore not possible to formulate conclusions on the sensitivity of MRI for ILC prior to biopsy. In a large multicenter trial by Bluemke et al. [
64] overall sensitivity for invasive cancer prior to biopsy was 91%, thus it might be expected that sensitivity for ILC prior to biopsy is also slightly lower. However, in most cases the indication for MRI is assessment of disease extent because of inconclusive findings at mammography or ultrasound. In conclusion, the sensitivity of MRI for ILC is higher than that achieved by any other modality, in direct comparison and validated by literature, and is equal to the overall sensitivity of MRI for malignant lesions of the breast. Only modern ultrasound examinations seem to have the ability to approach the performance of MRI in the detection of ILC [
57].
Morphology
The morphologic appearance of ILC on MRI ranged from 69% non-mass-like lesions to 95% mass-like lesions, thereby raising questions concerning the amount of heterogeneity in the description of morphology of lesions by radiologists. In fact, the general agreement on the description of lesion type according to the BI-RADS lexicon is only moderate [
14,
65]. In the current analysis, this is even further complicated because most authors did not specifically use the BI-RADS lexicon. Additionally, differences in scan techniques may have further affected the appearance of the lesion. However, in keeping with the above, the classification of lesion type is also highly variable on mammography, where the incidence of mass lesions ranges from 32 to 78% [
10,
45,
46,
48,
50,
51,
55].
The vast majority of the mass-like lesions described on MRI are irregular or spicular lesions. The eight patients with a dominant mass surrounded by multiple enhancing foci, as described by Schelfout et al. [
33], may present noncontiguous foci of disease without visible spiculae due to the absence of desmoplastic reaction, which is a well-known histopathological presentation [
8]. In all series only one round mass was described [
38], suggesting this to be a very rare presentation for ILC. This is consistent with findings in mammography by Le Gal et al. [
10], who described a round mass in only 2% of all patients where a mass was present (4/174) while the remainder was either classified as a spicular mass (54%) or poorly defined mass (44%).
Mammographic findings would therefore appear to correlate well with MRI findings. However, only one study allows direct comparison [
33]: of all lesions visible in this study on both mammography and MRI, 78% (18/23) were classified as mass-like by MRI, while only 48% (11/23) were classified as mass-like by mammography. Six masses on MRI were visible as architectural distortion on mammography and two as asymmetric density. In one case a lesion described as spicular mass on mammography was visible on MRI as multiple enhancing foci with interconnecting enhancing strands.
Non-mass-like ILC in mammography are typically described as architectural distortion or asymmetric density. In some cases microcalcifications are present, although these are often related to concurrent surrounding DCIS, sclerosing adenosis or fibrotic changes and might thus not be related to the presence of ILC [
45,
51,
55]. The descriptors currently used for non-mass-like lesions on MRI are diverse and include various types of abnormal enhancement, such as regional, ductal, segmental, and diffuse enhancement. According to Qayyum et al. [
30] the morphologic description of ILC on MRI has a good correlation to histopathologic findings. The non-mass-like presentation might specifically occur in cases where ILC grow in the classic pattern with cells arranged in a linear fashion along the ductuli.
It may thus be concluded that the appearance of most ILC on MRI and mammography is similar: most ILC are mass-lesions that have clear malignant properties. However, the more diffuse growing tumors are characterized by areas of unexpected enhancement and are more difficult to recognize. In a number of cases where no clear mass is visible on mammography, a mass-like lesion may be found on MRI [
33].
Kinetics
The relatively late contrast enhancement of ILC apparent in all studies presented here and mirrored by the relatively low values of K21 and EFP in the studies by Qayyum et al. [
30] and Yeh et al. [
38] must be taken into account when evaluating ILC. Standard subtraction images, generated from the pre-contrast and the first or second post-contrast acquisitions may be inconclusive as maximum enhancement is not achieved at this point in time and the lesion is thus not yet clearly visible. In fact, false-negative MRI in cases of ILC is usually contributed to inadequate enhancement of the tumor [
26,
35,
66]. The diffuse and often slow tumor growth, not requiring extensive neovascularization, may partly cause this difficult visualization [
1,
67,
68]. This is also clear from the relatively lower amount of vascular endothelial growth factor found in tumors with a lobular histology, which might also indicate a different signaling pathway in the formation of neovascular vessels in ILC, resulting in more mature and thus less leaky capillaries [
69], with consequently diminished or absent contrast enhancement.
Correlation
In the herein presented studies overestimation of lesion extent by mammography is rare, yet underestimation is more rule than exception. This is also confirmed by studies that specifically deal with mammography in cases of ILC. Yeatman et al. [
5] showed that mammography underestimated ILC by a mean of 12 mm. Uchiyama et al. [
51] reported 56% of all visible ILC on mammography to be underestimated and Veltman et al. [
52] showed 35–37% of all ILC to be mammographically understaged.
Ultrasound also tends to underestimate tumor size in the studies presented here. This finding is underlined by Tresserra et al. [
70] and more recently by Watermann et al. [
71], who documented a structural underestimation of 5.4 ± 12.2 mm in cases of ILC versus 1.4 ± 12.0 mm for cases of IDC. This might be partly due to the observation that US tends to underestimate larger tumors more than smaller tumors and low grade tumors more than high grade [
70], consistent with the finding that ILC usually presents with slightly larger and less aggressive tumors [
1,
5,
67,
72]. The current analysis shows that there is good correlation of tumor size measured on MRI compared to pathology. The various studies presented only moderately heterogeneous results.
In most cases MRI outperforms mammography and ultrasound in the assessment of disease extent. Most tumors are correctly classified as uni- or multifocal and multicentric disease is only seldom overestimated [
19,
32].
Additional lesions and effect on surgical treatment
Especially important in this analysis is the detection of additional lesions apart from the index lesion in patients with ILC. The co-existence of other invasive malignant lesions apart from the index lesion in the ipsilateral breast in 32% of patients only visualized by MRI is high. Moreover, the detection of contralateral cancer in another 7% of patients by MRI only, seems to make MRI indispensable. These findings are confirmed by the rate of change in treatment of the ipsilateral breast based on MRI. The fact that change in treatment was considered correct, as verified by pathologic findings in the specimen, in 88% of cases shows that ILC is often more extensive than appreciated on conventional imaging.
However, various authors have shown that there is no significant difference in disease free survival (DFS) or overall survival (OS) after BCT or mastectomy in patients with breast cancer. Although some authors report more local recurrence in patients with ILC after BCT [
2,
73], most authors showed that there is no difference in DFS or OS after BCT in ILC versus IDC [
74,
75]. On the other hand, Yeatman et al. [
5] reported a higher rate of conversion from lumpectomy to mastectomy in ILC compared to IDC (17.5% versus 6.9%). More recently, Molland et al. [
68] reported similar findings (37.2% versus 22.4%). Hussien et al. [
2] even reported failure of BCT in patients with ILC in 63% (34/54) of patients, resulting in conversion to mastectomy in 76% of failures (26/34). However, a very recent study by Morrow et al. [
76] showed that BCT did not fail more often in patients with ILC when corrected for age and tumor size, although they still observed a trend of more excisions in patients with ILC [OR 1.58 (0.89–2.79),
p = 0.12].
To date, there is no evidence suggesting increase in survival for patients with ILC due to the performance of MRI. What is then the added value of MRI? The rate of recurrence 10 years after BCT followed by radiotherapy is between 7 and 18% and is not significantly different from the rate of recurrence in case of IDC [
77,
78]. However, in view of the MRI findings (additional malignant lesions in 32% of patients), we can only conclude that in a large number of patients with ILC, surgery is not curative but merely debulking. As recurrence rates are fortunately much lower, we must assume that curative treatment is to be expected from adjuvant therapy. Unfortunately, because there is no possibility to determine which additional findings will respond to adjuvant therapy, the detection of additional lesions on MRI currently still requires a change of treatment when malignancy has been proven by core biopsy. This may further reduce the rate of recurrence in patients with ILC and may even improve survival. However, this requires confirmation in future studies.