Added value of contrast-enhanced spectral mammogram in assessment of suspicious microcalcification and grading of DCIS

Breast microcalcifications are one of the most difficult mammographic findings to assess. The purpose of this study is to assess the ability of contrast-enhanced spectral mammography in the assessment of suspicious microcalcification and in predicting the grade of DCIS. Three hundred and forty cases with suspicious microcalcification were reviewed in this study. We excluded 160 cases associated with masses. We enrolled 180 cases for analysis of suspicious microcalcification on mammograms with no underlying masses. We reviewed the microcalcification for their morphology, distribution, and associated pathological enhancement according to BI-RADS lexicon with pathology results reviewed and classified into benign and malignant which subdivided into low, intermediate, or high-grade DCIS or invasive carcinoma. Three hundred and forty cases with suspicious microcalcification were reviewed in this study. We excluded 160 cases associated with masses. Forty-five of 180 cases were benign, and 135/180 cases were malignant. Twenty-five of 135 cases were diagnosed as invasive breast carcinomas while 110/135 were ductal carcinoma in situ. From the latter, 110 patients with DCIS, 22/110 cases were low grade, 11/110 cases were intermediate grade, and 77/110 cases were high grade (44 with micro-invasion). A total of 25 invasive carcinomas showed pathological non-mass enhancement, 76/77 cases of high-grade DCIS, and 6/11 cases of intermediate-grade DCIS. No abnormal enhancement appeared with benign entities, low-grade DCIS, and 5/11 cases of intermediate DCIS. The diagnostic performance of CESM in anticipation of high grade in DCIS patients was sensitivity of 98%, specificity of 81.8%, and accuracy of 93.1%. CESM sensitivity, specificity, and accuracy in prediction of invasiveness or high-grade DCIS were 98.5%, 81.8%, and 87.5%, respectively. CESM can provide a fundamental contribution in the evaluation of suspicious microcalcification as high-grade DCIS or invasive component can present by non-mass enhancement, but enhancement paucity is favorable to diagnose benign lesion or non-invasive/low-grade DCIS.


Background
Breast calcifications are one of the common mammographic findings in screening and symptomatic populations. An approach to discriminate between benign and malignant breast calcifications to image analysis includes morphology, distribution, size, stability, and the number of calcifications [1].
Most of them have a benign origin presenting with characteristic benign morphology and need no further workup. Nevertheless, suspicious grouped calcifications can occur in ductal carcinoma in situ [1].
The American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) classifies calcifications on mammograms into three categories: typical benign, intermediate concern, and higher probability of malignancy [1][2][3].
Certain suspicious calcifications being micro <0.5 mm, with amorphous, coarse heterogeneous, fine pleomorphic, and fine linear or fine linear branching morphologies and grouped, segmental, or regional distribution were found to be of significant concern [4].
Most high-grade DCIS and low-or intermediate-grade invasive cancers can be observed by screening mammography. The diagnosis of high-grade DCIS before developing into high-grade invasive carcinoma was one of the added beneficial values of screening mammography programs [2].
CESM highlights the enhancement related to the breast cancer neovascularity similarly to dynamic contrast-enhanced breast MRI. This neovascularity is rapidly formed and causing contrast agent leakage [5].  The iodine uptake within the calcification calls attention to the plausible underlying pathologies. Nevertheless, the added value is still vague [6].
CESM is offering an accessible substitute for suspicious findings that may need CE-MRI with the benefit to conceive microcalcifications in low-energy images and accompanied enhancement [7][8][9].
CESM can be specifically indicated as annual screening for women who underwent chest radiation therapy during young age, who have a higher incidence of DCIS with possible low neoangiogenesis that may be overlooked at CE-MRI [10,11].
This study aims to assess the ability of CESM in the assessment of suspicious microcalcification and in predicting the grade of DCIS.

Methods
This study is a prospective analytical study. Three hundred and thirty females were incorporated with 340 suspicious microcalcifications. The multidisciplinary "Breast Cancer Hospital" ethical committee approved the study. Enlightened written consent was taken from all participants.

Patients
Patients included were females with suspicious microcalcifications. We excluded 160 cases associated with masses. We enrolled 180 cases for analysis of suspicious non-mass-associated microcalcification on mammograms. CESM was requested aiming for both clarifications of its significance and prediction of related malignancy.

Image evaluation
A thorough review of the low-energy mammography images and the post-processed contrast images was performed. Two radiologists analyzed and interpreted CESM in accordance with the latest MRI BI-RADS lexicon update (because of no contrast-enhanced mammographic ACR lexicon) [12]. All patients underwent biopsy+/-surgery.

Histopathologic examination
Histopathologic diagnosis of all cases and grading of DCIS were carried out based on morphological examination of The final histopathologic result of malignant cases was based on examination of the surgical specimen, while that of benign/atypical cases was based on either tissue biopsies or surgical specimen examination [13].
Pathological non-mass enhancement was associated with all 25 invasive carcinomas, 76/77cases of highgrade DCIS, and 6/11 cases of intermediate grade DCIS. No pathological enhancement was elicited with benign entities, all low-grade DCIS, and 5/11 cases of intermediate DCIS (Table 3).
We identified contrast enhancement in 109/180 microcalcifications. The presence of enhancing lesions underlying microcalcifications was significantly higher in malignant than in benign lesions (p-value 0.05).
Diagnostic performance of CESM in the prediction of high grade in DCIS patients was sensitivity of 98%, specificity of 81.8%, and accuracy of 93.1%. CESM sensitivity, specificity, and accuracy in the prediction of invasiveness or high-grade DCIS were 98.5%, 81.8%, and 87.5% respectively (Tables 4 and 5).

Discussion
Mammography remains the gold standard imaging modality in detecting breast microcalcifications. Discrimination between benign and malignant microcalcifications according to the morphology and distribution has been strengthened and gives a confident diagnosis if associated with pathological contrast enhancement in a rapid CESM modality compared to breast MRI.
Studies have shown that CESM is superior to FFDM in overall performance in cancer detection; the estimated sensitivity of CESM was 98% (95% CI = 96-100), with a reported estimated specificity of 58% (95% CI = 38-77) [14]. However, most studies included all breast lesions, not only specific entities as suspicious calcifications.
Houben et al. included 147 women in their study; diagnostic performances of CESM in non-mass microcalcifications were sensitivity of 93.8%, specificity of 36.6%, PPV of 54%, and NPV of 88.2% [15].
In the current study, pathological non-mass enhancement was associated with all invasive carcinoma, almost all cases of high-grade DCIS, and some cases of intermediate grade DCIS. No pathological enhancement was elicited with benign entities, all low-grade DCIS, and some cases of intermediate DCIS. As compared to Cheung et al., all IDC (100%) and some DCIS (84.21%) showed enhancement, but the other 15.79% DCIS did not show enhancement, while Houben et al. did not observe any differences between the amounts of enhancement between invasive and in situ breast cancers, and approximately 11% of the high-grade DCIS did not show any enhancement [6,15].
In the current study, the grouped amorphous and fine pleomorphic microcalcifications associated with enhancement were associated with high-grade DCIS and invasive carcinoma (46%) compared to the other morphological entities, as compared to Cheung et al., who found that the pleomorphous microcalcifications with enhancement showed higher positive predictive value (90.00% vs 46.15%, p = 0.013) and higher cancer probability than the amorphous microcalcifications (46.3% vs 15.1%) [6].

Conclusion
CESM can provide a fundamental contribution in the evaluation of suspicious microcalcification as highgrade DCIS or invasive component can present by non-mass enhancement, but enhancement paucity is favorable to diagnose benign lesion or non-invasive/ low-grade DCIS.