MRI and comparison mammography: a worthy diagnostic alliance for breast microcalcifications?

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Acta Radiol OnlineFirst, published on May 20, 2015 as doi:10.1177/0284185115585036

Original Article

MRI and comparison mammography: a worthy diagnostic alliance for breast microcalcifications?

Acta Radiologica 0(0) 1–9 ! The Foundation Acta Radiologica 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185115585036 acr.sagepub.com

Dijana Brnic1, Darko Brnic2, Ivan Simundic1, Lucija Vanjaka Rogosic3 and Tade Tadic1

Abstract Background: There is a lack of data concerning diagnostic performance of magnetic resonance imaging (MRI) in patients with new or increasing microcalcifications. Purpose: To evaluate suspicious microcalcifications by using comparison mammography, MRI, and a combination of both methods. Material and Methods: Our study group consisted of 55 patients with mammographically detected BI-RADS (Breast Imaging Reporting and Data System) 3–5 microcalcifications for whom comparison mammograms were available. All patients underwent breast MRI before SVAB (stereotactic vacuum-assisted biopsy). Diagnostic performances of comparison mammography and MRI were evaluated, as well as the combination of the respective imaging findings. Results: Of the 55 microcalcification cases, 35 showed progression and 20 were stable between interval screenings. The negative predictive value (NPV) of comparison mammography was 100%, whereas the NPV of MRI was 92%. However, the specificity of combination of findings was 97%, significantly higher than the 42% specificity of comparison mammography (P < 0.001). Additionally, the positive predictive value of combination of findings was 93% versus 44% of comparison mammography (P ¼ 0.001). Conclusion: A biopsy is recommended when MRI positive lesion corresponding the area of new or increasing mammographic microcalcifications is detected. Patients with stable microcalcifications can continue follow-up mammography, regardless of MRI result.

Keywords Magnetic resonance imaging (MRI), comparison, mammography, microcalcifications, descriptors, stability Date received: 8 April 2014; accepted: 7 April 2015

Introduction Microcalcifications are a valuable mammographic feature in screening for breast carcinoma. Nearly half of the clinically occult breast carcinomas detected on mammography are associated with microcalcifications (1). High percentage of ductal carcinoma in situ (DCIS) lesions has been found to appear only as microcalcifications at mammography (2,3). Several studies have concluded that the use of microcalcification morphologic and distribution descriptors as proposed in the BIRADS Lexicon (4th edition) can aid in stratifying the risk of malignancy (4–7). Further improvements in the interpretation of mammographically detected microcalcifications are still preferred, as only one-third

of mammographic microcalcifications proceeded to SVAB are malignant (8). One can notice that stability descriptors are not among microcalcification descriptors appreciated in the BI-RADS lexicon (9). Studies specifically reporting stability descriptors of breast 1 Department of Diagnostic and Interventional Radiology, University Hospital Center Split, Croatia 2 Department of Internal Medicine, University Hospital Center Split, Croatia 3 Private Dermatovenerology Clinic, Split, Croatia

Corresponding author: Dijana Brnic, Department of Diagnostic and Interventional Radiology, University Hospital Center Split, Spinciceva 1, Split, Croatia. Email: [email protected]

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microcalcifications are very few (4,10). All the same, comparison with previously obtained mammograms is recommended, according to the 2013 American College of Radiology practice guidelines (11). Breast MRI is also used in the evaluation of mammographically suspicious microcalcifications. Recently reported values of sensitivity are in the range of 45– 87% and the specificity is in the range of 68–100% (12–16). MRI is capable of detecting an invasive component in DCIS or the extent and multifocality of malignancy (17). Yet, MRI cannot reliably diagnose malignancy as wide spectrum of benign breast conditions simulate malignant lesion on MRI (18). Whether bilateral breast MRI can be a diagnostic alternative to SVAB for women with increasing or newly developed BI-RADS 3–5 microcalcifications is unknown. The purpose of our study was to evaluate the diagnostic performance of MRI in women with comparison mammograms demonstrating new or increasing microcalcifications.

The average interval between screening mammograms was 25 months (range, 8–46 months).

MRI technique Bilateral breast MRI was performed with the patients prone in a 1,5 T MRI system (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) with a dedicated bilateral breast surface coil. After obtaining T2weighted imaging with fat suppression (TR/TE, 5600/ 59) with 3 mm slice thickness in axial plane, T1weighted 3D gradient echo (GRE) imaging with fat suppression (TR/TE, 4.43/1.7; flip angle, 10 ; field of view, 340 mm; matrix, 340 340; acquired voxel size, 1.1 0.8 1.7 mm3) was performed before and four times after the bolus injection of 0.1 mmol/kg of a gadopentetate dimeglumine (Gd-DTPA, Magnevist, Bayer HealthCare, Leverkusen, Germany). Following this, 20 mL saline was injected. The temporal resolution was 60 s per dynamic acquisition. Subtracted images from the dynamic sequence and MIP (maximum intensity projections) were used for MRI analyses.

Material and Methods Participants

SVAB

We defined the study participants as those women presenting with BI-RADS 3–5 microcalcifications and old mammograms available for comparison. Data from screening and diagnostic mammography were used, whereby old mammograms were obtained from computerized mammography records at our facility and from the women herself. Regarding old mammograms, only the most recent images for participants with multiple examinations were acquired. Each participant underwent breast MRI and was scheduled to receive SVAB in accordance with an institutional review board, and provided informed consent. The results of SVAB and surgical breast biopsy followed by 1-year follow-up mammography were the reference standard for lesions evaluation. High-risk lesions were confirmed by means of surgical excision. Between January 2010 and December 2012, 109 women with BI-RADS 3–5 microcalcifications were detected in our institution. Fifty-four women were excluded for the following reasons: 41 because copies of the previous mammograms were incomplete or unavailable, five because mammographic follow-up of at least 12 months was not performed after biopsy, two did not undergo MRI, and two withdrew from the study. Four women who had previously undergone contralateral mastectomy were also excluded. The final group consisted of 55 women (average age, 54 years; age range, 38–75 years). With regard to family history of breast cancer, most of the participants (78.2%; 43/55) were at average risk of breast cancer.

SVAB was performed with the patients upright on a digital stereotactic table (Mammomat Nova 3000; Siemens AG, Erlangen, Germany) using Opdima vacuum-assisted biopsy device with 11-gauge probes. A variable number of specimens, in the range of 10–20 (with mean number of 13.2 per procedure), were obtained.

Interpretation of comparison mammograms Two experienced mammographic radiologists independently evaluated present mammograms blinded to the participants information using BI-RADS lexicon (9) and guidelines proposed by Burnside et al. (4). Images from previous mammography were reviewed and compared with present mammograms to determine microcalcifications stability descriptor. For each case, microcalcifications screening interval change in number, more suspicious morphology or distribution were noted. Stability descriptor could be assigned one of the following types: new/increasing (including any of the above changes), stable (without notable change), and decreasing. On the basis of screening interval change, final BI-RADS category was often upgraded. In some cases, stable microcalcifications were classified as positive on comparison mammography. According to BI-RADS, overall assessment should be based on the most suspicious descriptor assigned. Final mammographic BI-RADS categories based on morphology, distribution, and stability of microcalcifications are presented in Table 1.




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Table 1. Mammographic BI-RADS final assessment category in 55 microcalcification cases. BI-RADS category Microcalcifications descriptors Morphology Punctate Amorphous Coarser heterogeneous Fine pleomorphic Fine linear Total Distribution Diffuse Regional Cluster Segmental Linear Total Stability Stable New/increasing Total

3

4

5

Total

4 12 0 0 0 16

0 9 13 15 2 39

0 0 0 0 0 0

4 21 13 15 2 55

0 4 8 4 0 16

0 2 21 15 1 39

0 0 0 0 0 0

0 6 29 19 1 55

12 4 16

8 31 39

0 0 0

20 35 55

Data are number of lesions.

under evaluation. In addition, to evaluate the utility of combined use of MRI and comparison mammography, further analyses were made by combining the respective imaging findings. Lesions with invasive carcinoma, DCIS and DCIS with microinvasion were accepted as malignant diagnoses; others, including high-risk lesions (atypical ductal or lobular hyperplasia, FEA, lobular carcinoma in situ, and phyllodes tumor) were accepted as benign diagnoses. A BI-RADS assessment of 4 or 5 was considered as positive for comparison mammography and additional MRI, while an assessment of BI-RADS 1, 2, or 3 was considered as negative. For combined analysis, patients with malignant result at final pathology and/or follow-up, positive result at MRI and comparison mammograms demonstrating new or increasing microcalcifications were accepted as ‘‘true positive’’, while all other combinations of MRI and comparison mammography results were accepted as ‘‘true negative’’. To analyze differences between sensitivity or specificity, we used McNemar’s test. Z-test was used to analyze differences between PPVs or NPVs. Relationship of two nominal, categorical variables was tested by 2 test, with phi coefficient given for statistically significant results in case of two categories. Level of significance was set to 5% (P < 0.05), and all confidence intervals were given on the 95% level. Analyses were carried out using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) statistical software package.

MRI interpretation MR examinations were interpreted by one breast MRI experienced radiologist. Before beginning each MR assessment, the radiologist was provided with the breast microcalcifications location (quadrant and depth), but had no access to data in regard to personal history of breast cancer, prior MRI and other mammographic findings (breast density, microcalcifications descriptors, and final classification). All MRI features were reported in accordance with the BI-RADS MR lexicon (19). The MRI findings were evaluated for the presence or absence of an enhancing lesion and symmetry of breast tissue contrast enhancement on bilateral imaging. Regarding BI-RADS descriptors for MRI, masses were described by margin and enhancement kinetics, and distribution and internal enhancement were evaluated in non-mass type of lesions. Interpretation criteria proposed by Akita et al. (13) were used.

Results Of the 55 microcalcification cases, 17 (30.9%) were malignant and 38 (69.1%) were benign. Histopathologic and MRI findings sorted by stability descriptors are shown in Table 2.

Comparison mammography findings Most of the microcalcification cases (64%; 35/55) demonstrated progression between interval screenings. None of cases that we analyzed had decreasing microcalcifications. There was significant difference in histopathologic result regarding stability descriptors. All lesions (100%; 20/20) with stable microcalcifications were benign, whereas all malignant lesions (100%; 17/ 17) exhibited new or increasing microcalcifications at mammography (P < 0.001, 2).

Data analysis and statistical evaluation

MR and combined imaging findings

All examinations were classified as positive or negative and the diagnoses were used to calculate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two imaging methods

Overall, 65.5% (36/55) cases demonstrated enhancement (focus, mass, or non-mass type) in the area of mammographic microcalcifications and were classified as asymmetric on bilateral MRI (BI-RADS MRI



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Table 2. Histopathology and MRI findings in 55 microcalcification cases sorted by stability descriptors. MRI type of lesion

BI-RADS MR category*

Overall number Focus Mass Non-mass NE (n ¼ 55) (n ¼ 8) (n ¼ 10) (n ¼ 18) (n ¼ 19) 1 (n ¼ 16) 2 (n ¼ 3) 3 (n ¼ 17) 4 (n ¼ 4) 5 (n ¼ 15) 17 Malignant with new/increasing microcalcifications IDC 6 DCIS-MI 3 DCIS 8 18 Benign with new/increasing microcalcifications FCC 7 FA 3 HUT 4 Normal epitel 1 FEA 2 Sclerosing adenosis 1 Benign with stable microcalcifications 20 FCC 2 FA 2 HUT 4 Normal epitel 6 FEA 3 Sclerosing adenosis 1 RS 1 Lobular hyperplasia 1

0

5

9

3

2

0

1

2

12

0 0 0 6

3 1 1 1

3 2 4 4

0 0 3 7

0 0 2 5

0 0 0 2

0 0 1 10

0 2 0 1

6 1 5 0

1 2 2 0 1 0

0 1 0 0 0 0

3 0 0 0 0 1

3 0 2 1 1 0

2 0 1 1 1 0

1 0 1 0 0 0

3 3 2 0 1 1

1 0 0 0 0 0

0 0 0 0 0 0

2 0 0 1 0 1 0 0 0

4 0 2 0 0 0 1 1 0

5 1 0 3 0 1 0 0 0

9 1 0 0 6 1 0 0 1

9 1 0 0 6 1 0 0 1

1 0 0 1 0 0 0 0 0

6 0 2 2 0 2 0 0 0

1 1 0 0 0 0 0 0 0

3 0 0 1 0 0 1 1 0

Data are number of lesions. *Symmetry on bilateral MRI and corresponding BI-RADS MR categories: 1, no abnormal enhancement; 2, symmetric enhancement; 3, 4, and 5, asymmetrical enhancement. DCIS-MI, ductal carcinoma in situ with microinvasion; FCC, fibrocystic change; FA, fibroadenoma; FEA, flat epithelial atypia; HUT, hyperplasia of usual type; IDC, invasive ductal carcinoma; NE, non-enhancement in the area corresponding microcalcifications at mammography; RS, radial scar.

categories 3–5). Table 3 shows final BI-RADS MR categories for the 28 enhancing lesions (10 of mass and 18 of non-mass type) based on the BI-RADS descriptors for MRI. Table 4 summarizes diagnostic values by imaging method and combined analysis, as well as data for false and positive findings. Combination of MRI test result and comparison mammography finding helped reduce the number of false positive diagnoses to only one case in our study. This case was subsequently identified as FCC (Fig. 1). Significant difference was found between malignant and benign microcalcifications in combined analysis. Malignant lesion was most likely to be found in participants with positive MRI and new or increasing

microcalcifications (Fig. 2) as opposed to participants with any other combination of MRI and comparison mammography finding (P < 0.001, 2).

Diagnostic validity of the imaging methods The addition of MRI to mammography significantly improved specificity and PPV, compared to mammography (specificity, P < 0.001, McNemar’s test; PPV, Z-value ¼ 2.15; P ¼ 0.032), and the combination of imaging findings improved specificity and PPV even more (specificity, P < 0.001, McNemar’s test; PPV, Z-value ¼ 3.26; P ¼ 0.001). There were no significant differences in specificity and in PPV between



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Table 3. MRI features and final BI-RADS categories in non-mass and mass type of lesions (n ¼ 28). Mass type (n ¼ 10)

Non-mass type (n ¼ 18)

Final assessment category BI-RADS MR 3

Margins/enhancement kinetics 3 smooth/persistent

BI-RADS MR 4

1 irregular/plateau

BI-RADS MR 5

4 irregular/washout, 2 spiculated/washout

Internal enhancement/distribution 2 stippled/diffuse, 1 reticular/diffuse, 2 stippled/regional, 1 clumped/regional 2 homogeneous/segmental/, 1 clustered ring/focal 5 clumped/segmental, 3 clustered ring/ segmental, 1 homogeneous/ductalbranching

Data are number of lesions.

Table 4. Diagnostic validity of the imaging methods in total number of participants (n ¼ 55).

Comparison mammography Additional MRI Combined analysis*

Positive

Negative

Diagnostic values

True

False

False

True

Sensitivity

Specificity

Positive PV

Negative PV

17 14 14

22 5 1

0 3 3

16 33 37

100% (81–100%) 82% (61–100%) 82% (63–88%)

42% (34–42%) 87% (77–92%) 97% (89–100%)

44% (35–44%) 74% (55–85%) 93% (72–100%)

100% (80–100%) 92% (82–98%) 93% (85–95%)

Data are number of lesions and percentages with 95% confidence interval in parentheses. *Malignant lesions with MRI positive result and new or increasing microcalcifications at mammography were accepted as true positive. PV, predictive value.

Fig. 1. False positive case example for combined analysis: fibrocystic change in a 40-year-old woman. (a) Initial mammogram of the left breast, mediolateral oblique view: there is no evidence of suspicious microcalcifications in the retro-areolar region (arrow). (b) Suspicious microcalcifications are seen on the follow-up mediolateral mammogram (arrow) which was obtained 28 months later. (c) Subtracted MR images of bilateral breast reveal non-mass type of enhancement in the area of microcalcifications. This case was classified as positive on comparison mammography (BI-RADS category 4) and additional MR (BI-RADS MR category 4).



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Fig. 2. True positive case example for combined analysis: DCIS with microinvasion in the left breast of a 67-year-old woman. (a) Initial craniocaudal mammogram without suspicious microcalcifications in the evaluated area (arrow). (b) A follow-up mammogram obtained 35 months later shows suspicious microcalcifications as well as the developing density in the inner quadrant (arrow). (c) Non-mass type of enhancement is shown on subtracted MRI. This case was determined to be positive on comparison mammography (BI-RADS category 4) and additional MRI (BI-RADS MR category 5).

combination of imaging findings and additional MRI (specificity, P ¼ 0.125, McNemar’s test; PPV, Zvalue ¼ 1.44; P ¼ 0.150). Three cases were missed by MRI and in combination of findings with a final diagnosis of DCIS. In one case, a low-grade non-comedo DCIS of 7 mm was confirmed after lumpectomy, whereas final pathologic analyses in the remaining two cases yielded high-grade noncomedo DCIS lesions measuring 5 and 8 mm (Fig. 3). Sensitivity was reduced with MRI and in combination of imaging findings, compared to mammography; however, the difference was not significant (P ¼ 0.250, McNemar’s test). Regarding NPV, there was no significant difference between combination of imaging findings and comparison mammography (Z ¼ 1.13; P ¼ 0.259) and between additional MRI and comparison mammography (Z ¼ 1.19; P ¼ 0.234).

Discussion Although the NPV of comparison mammography was 100% in our study, the estimated predictive value of a positive finding was only 44%, indicating that comparison mammography is not the most efficacious for detecting malignancy in BI-RADS 3-5 microcalcifications. Additional bilateral breast MRI and combination of

imaging findings improved microcalcifications characterization compared with mammography, as was shown by a significant increase in specificity and in PPV, respectively. The detection of MRI positive lesion in the area of mammographic microcalcifications with screening interval progression becomes the most predictive feature of malignancy in our study, with a PPV of 93%. A prior study that used bilateral breast MRI and proposed detailed guidelines for detection of intraductal cancers on MRI in mammographically suspicious microcalcifications, had similar sensitivity (85%) and higher specificity (100%) compared with the values in our study (82% and 87%, respectively) (13). Using MRI interpretation criteria from this study, we missed three cases with a final diagnosis of DCIS, and, especially, two of high-grade. Molecular and genetic evidence exist and show that high-grade DCIS is an aggressive subtype and is more prone to progress to high-grade invasive carcinoma (20). Because contrast enhancement is considered as a biomarker of angiogenic and protease activity, DCIS lesions depicted on MRI may have a higher probability of progressing to invasive carcinoma than mammographically detected lesions (21). Kuhl et al. reported that the sensitivity of MRI for the detection of DCIS, especially of



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Fig. 3. False negative case example for combined analysis: a 75-year-old woman with high-grade non-comedo DCIS measuring 8 mm. (a) Right craniocaudal mammogram demonstrates no abnormalities in the outer quadrant (arrow). (b) Craniocaudal mammogram obtained 23 months later demonstrates newly developed microcalcifications classified as BI-RADS category 4. (c) Subtracted MRI of bilateral breast without abnormal enhancement in the area of microcalcifications at mammography. Because of asymmetrical background parenchymal enhancement in the right breast compared to left this case was classified as BI-RADS MR 3.

high-grade lesions, exceeds that of mammography (92% versus 56%) (22). The causes of underrating of two high grade DCIS in our study are uncertain. In a study by Chan et al., two MRI false-negative DCIS of high-grade with non-comedo morphology were identified in a group of 31 patients with histologically proven pure DCIS (23). These two DCIS measured 1.4 and 1.1 cm and both were likely obscured due to strong background parenchymal enhancement. Such a strong background enhancement also occurred in a high grade DCIS missed by MRI in our study. It has been recommended to classify the background enhancement into four categories so that information about the expected MR sensitivity can be obtained (17). Also, a careful evaluation of the early postcontrast acquisition is necessary in order to detect carcinoma enhancing earlier than the surrounding parenchyma. Another explanation is that we used suboptimal MR contrast agent. A significantly superior diagnostic performance (P 0.0094) was confirmed for Multihance over Magnevist in a study that used identical acquisition and image interpretation (24).

Our analysis of benign microcalcifications revealed four MRI false positive cases in the stable group (20%) compared to only one in the new/increasing group (5.6%). Millet et al. attributed misinterpretation of artifacts, confusion between normal enhancing structures and tumors as well as the insufficient use of BI-RADS lexicon as leading reasons for false-positive MRI diagnoses (25). In order to decrease the rate of false-positive findings, those authors suggested the following criteria for benign non-mass type enhancement: symmetry on bilateral imaging, presence of several cysts, diffuse enhancement without clinical, ultrasonic or mammographic signs, and stippled enhancement in regional distribution in non-menopausal patient without strong risk factors and associated mammographic or ultrasonic abnormalities. There are several limitations to our study. First, there is a selection bias, because only those participants with suspicious microcalcifications that had previous mammograms available for comparison were included. Also, women with contralateral mastectomy were excluded, thus, we were not able to identify if personal



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history of breast carcinoma could affect the likelihood of malignancy. Martini et al. found that PPV of biopsy yielding cancer (35.7%) in women with personal history of breast carcinoma was triple that of the women with a genetic or family history (26). Second, our MR examinations were not entirely performed by current standards; we believe that an optimal MR contrast agent would have help to depict breast abnormalities more accurately. Third, we did not perform a detailed analysis regarding morphology and enhancement kinetics of the MRI enhancing lesions, nor did we correlate MRI findings and stability descriptors with the microcalcifications morphologic and distribution descriptors due to the relatively small number of cases. In conclusion, bilateral breast MRI is useful in patients with comparison mammograms demonstrating new or increasing microcalcifications and biopsy can be recommended when MRI positive lesions corresponding the area of new or increasing microcalcifications is detected. Acknowledgements The authors thank Proffesor Stipan Jankovic, MD, for general support and Biometrika Healthcare Research, Croatia, for statistical data analysis.

Conflict of interest None declared.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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