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1.  High-resolution 3D micro-CT imaging of breast microcalcifications: a preliminary analysis 
BMC Cancer  2014;14:9.
Background
Detection of microcalcifications on mammograms indicates the presence of breast lesion, and the shapes of the microcalcifications as seen by conventional mammography correlates with the probability of malignancy. This preliminary study evaluated the 3D shape of breast microcalcifications using micro-computed tomography (micro-CT) and compared the findings with those obtained using anatomopathological analysis.
Methods
The study analyzed breast biopsy samples from 11 women with findings of suspicious microcalcifications on routine mammograms. The samples were imaged using a micro-CT (SkyScan 1076) at a resolution of 35 μm. Images were reconstructed using filtered back-projection and analyzed in 3D using surface rendering. The samples were subsequently analyzed by the pathology service. Reconstructed 3D images were compared with the corresponding histological slices.
Results
Anatomopathological analysis showed that 5 of 11 patients had ductal breast carcinoma in situ. One patient was diagnosed with invasive ductal carcinoma.
Individual object analysis was performed on 597 microcalcifications. Malignant microcalcifications tended to be thinner and to have a smaller volume and surface area, while their surface area-to-volume ratio was greater than that of benign microcalcifications. The structure model index values were the same for malignant and benign microcalcifications.
Conclusions
This is the first study to use micro-CT for quantitative 3D analysis of microcalcifications. This high-resolution imaging technique will be valuable for gaining a greater understanding of the morphologic characteristics of malignant and benign microcalcifications. The presence of many small microcalcifications can be an indication of malignancy. For the larger microcalcifications, 3D parameters confirmed the more irregular shape of malignant microcalcifications.
doi:10.1186/1471-2407-14-9
PMCID: PMC3893600  PMID: 24393444
Breast cancer; Biopsies; X-ray micro-CT; Microcalcifications; 3D morphological analysis
2.  New relationships between breast microcalcifications and cancer 
British Journal of Cancer  2010;103(7):1034-1039.
Background:
Breast microcalcifications are key diagnostically significant radiological features for localisation of malignancy. This study explores the hypothesis that breast calcification composition is directly related to the local tissue pathological state.
Methods:
A total of 236 human breast calcifications from 110 patients were analysed by mid-Fouries transform infrared (FTIR) spectroscopy from three different pathology types (112 invasive carcinoma (IC), 64 in-situ carcinomas and 60 benign). The biochemical composition and the incorporation of carbonate into the hydroxyapatite lattice of the microcalcifications were studied by infrared microspectroscopy. This allowed the spectrally identified composition to be directly correlated with the histopathology grading of the surrounding tissue.
Results:
The carbonate content of breast microcalcifications was shown to significantly decrease when progressing from benign to malignant disease. In this study, we report significant correlations (P<0.001) between microcalcification chemical composition (carbonate content and protein matrix : mineral ratios) and distinct pathology grades (benign, in-situ carcinoma and ICs). Furthermore, a significant correlation (P<0.001) was observed between carbonate concentrations and carcinoma in-situ sub-grades. Using the two measures of pathology-specific calcification composition (carbonate content and protein matrix : mineral ratios) as the inputs to a two-metric discriminant model sensitivities of 79, 84 and 90% and specificities of 98, 82 and 96% were achieved for benign, ductal carcinoma in situ and invasive malignancies, respectively.
Conclusions:
We present the first demonstration of a direct link between the chemical nature of microcalcifications and the grade of the pathological breast disease. This suggests that microcalcifications have a significant association with cancer progression, and could be used for future objective analytical classification of breast pathology. A simple two-metric model has been demonstrated, more complex spectral analysis may yeild greater discrimination performance. Furthermore there appears to be a sequential progression of calcification composition.
doi:10.1038/sj.bjc.6605873
PMCID: PMC2965876  PMID: 20842116
breast cancer; calcifications; carbonate; DCIS; diagnose; FTIR; grade
3.  Application of Raman spectroscopy to identify microcalcifications and underlying breast lesions at stereotactic core needle biopsy 
Cancer research  2013;73(11):3206-3215.
Microcalcifications are a feature of diagnostic significance on a mammogram and a target for stereotactic breast needle biopsy. Here, we report development of a Raman spectroscopy technique to simultaneously identify microcalcification status and diagnose the underlying breast lesion, in real-time, during stereotactic core needle biopsy procedures. Raman spectra were obtained ex vivo from 146 tissue sites from fresh stereotactic breast needle biopsy tissue cores from 33 patients, including 50 normal tissue sites, 77 lesions with microcalcifications, and 19 lesions without microcalcifications, using a compact clinical system. The Raman spectra were modeled based on the breast tissue components and a support vector machine framework was used to develop a single-step diagnostic algorithm to distinguish normal tissue, fibrocystic change (FCC), fibroadenoma (FA) and breast cancer, in the absence and presence of microcalcifications. This algorithm was subjected to leave-one-site-out cross-validation, yielding a positive predictive value, negative predictive value, sensitivity and specificity of 100%, 95.6%, 62.5% and 100% for diagnosis of breast cancer (with or without microcalcifications) and an overall accuracy of 82.2% for classification into specific categories of normal tissue, FCC, FA or breast cancer (with and without microcalcifications). Notably, the majority of breast cancers diagnosed are ductal carcinoma in situ (DCIS), the most common lesion associated with microcalcifications, which could not be diagnosed using previous Raman algorithm(s). Our study demonstrates the potential of Raman spectroscopy to concomitantly detect microcalcifications and diagnose associated lesions, including DCIS, and thus provide real-time feedback to radiologists during such biopsy procedures, reducing non-diagnostic and false negative biopsies.
doi:10.1158/0008-5472.CAN-12-2313
PMCID: PMC3754785  PMID: 23729641
Raman; spectroscopy; breast; cancer; microcalcifications
4.  Correlation between imaging and pathology in ductal carcinoma in situ of the breast 
Background
It is helpful in planning treatment for patients with ductal carcinoma in situ (DCIS) if the size and grade could be reliably predicted from the mammography. The aims of this study were to determine if the type of calcification can be best used to predict histopathological grade from the mammograms, to examine the association of mammographic appearance of DCIS with grade and to assess the correlation between mammographic size and pathological size.
Methods
Mammographic films and pathological slides of 115 patients treated for DCIS between 1986 and 2000 were reviewed and reclassified by a single radiologist and a single pathologist respectively. Prediction models for the European Pathologist Working Group (EPWG) and Van Nuys classifications were generated by ordinal regression. The association between mammographic appearance and grade was tested with the χ2-test. Relation of mammographic size with pathological size was established using linear regression. The relation was expressed by the correlation coefficient (r).
Results
The EPWG classification was correctly predicted in 68%, and the Van Nuys classification in 70% if DCIS was presented as microcalcifications. High grade was associated with presence of linear calcifications (p < 0.001). Association between mammograhic- and pathological size was better for DCIS presented as microcalcifications (r = 0.89, p < 0.001) than for DCIS presented as a density (r = 0.77, p < 0.001).
Conclusions
Prediction of histopathological grade of DCIS presenting as microcalcifications is comparable using the Van Nuys and EPWG classification. There is no strict association of mammographic appearance with histopathological grade. There is a better linear relation between mammographic- and pathological size of DCIS presented as microcalcifications than as a density, although both relations are statistically significant.
doi:10.1186/1477-7819-2-4
PMCID: PMC394346  PMID: 15018618
ductal carcinoma in situ; imaging; size; prediction; pathological classification; breast
5.  Independent predictors of breast malignancy in screen-detected microcalcifications: biopsy results in 2545 cases 
British Journal of Cancer  2011;105(11):1669-1675.
Background:
Mammographic microcalcifications are associated with many benign lesions, ductal carcinoma in situ (DCIS) and invasive cancer. Careful assessment criteria are required to minimise benign biopsies while optimising cancer diagnosis. We wished to evaluate the assessment outcomes of microcalcifications biopsied in the setting of population-based breast cancer screening.
Methods:
Between January 1992 and December 2007, cases biopsied in which microcalcifications were the only imaging abnormality were included. Patient demographics, imaging features and final histology were subjected to statistical analysis to determine independent predictors of malignancy.
Results:
In all, 2545 lesions, with a mean diameter of 21.8 mm (s.d. 23.8 mm) and observed in patients with a mean age of 57.7 years (s.d. 8.4 years), were included. Using the grading system adopted by the RANZCR, the grade was 3 in 47.7% 4 in 28.3% and 5 in 24.0%. After assessment, 1220 lesions (47.9%) were malignant (809 DCIS only, 411 DCIS with invasive cancer) and 1325 (52.1%) were non-malignant, including 122 (4.8%) premalignant lesions (lobular carcinoma in situ, atypical lobular hyperplasia and atypical ductal hyperplasia). Only 30.9% of the DCIS was of low grade.
Mammographic extent of microcalcifications >15 mm, imaging grade, their pattern of distribution, presence of a palpable mass and detection after the first screening episode showed significant univariate associations with malignancy. On multivariate modeling imaging grade, mammographic extent of microcalcifications >15 mm, palpable mass and screening episode were retained as independent predictors of malignancy. Radiological grade had the largest effect with lesions of grade 4 and 5 being 2.2 and 3.3 times more likely to be malignant, respectively, than grade 3 lesions.
Conclusion:
The radiological grading scheme used throughout Australia and parts of Europe is validated as a useful system of stratifying microcalcifications into groups with significantly different risks of malignancy. Biopsy assessment of appropriately selected microcalcifications is an effective method of detecting invasive breast cancer and DCIS, particularly of non-low-grade subtypes.
doi:10.1038/bjc.2011.466
PMCID: PMC3242612  PMID: 22052156
breast cancer; screening; mammography; microcalcifications
6.  Imprint cytology on microcalcifications excised by Vacuum-Assisted Breast Biopsy: A rapid preliminary diagnosis 
Background
To evaluate imprint cytology in the context of specimens with microcalcifications derived from Vacuum-Assisted Breast Biopsy (VABB).
Patients and methods
A total of 93 women with microcalcifications BI-RADS 3 and 4 underwent VABB and imprint samples were examined. VABB was performed on Fischer's table using 11-gauge Mammotome vacuum probes. A mammogram of the cores after the procedure confirmed the excision of microcalcifications. For the application of imprint cytology, the cores with microcalcifications confirmed by mammogram were gently rolled against glass microscope slides and thus imprint smears were made. For rapid preliminary diagnosis Diff-Quick stain, modified Papanicolaou stain and May Grunwald Giemsa were used. Afterwards, the core was dipped into a CytoRich Red Collection fluid for a few seconds in order to obtain samples with the use of the specimen wash. After the completion of cytological procedures, the core was prepared for routine histological study. The pathologist was blind to the preliminary cytological results. The cytological and pathological diagnoses were comparatively evaluated.
Results
According to the pathological examination, 73 lesions were benign, 15 lesions were carcinomas (12 ductal carcinomas in situ, 3 invasive ductal carcinomas), and 5 lesions were precursor: 3 cases of atypical ductal hyperplasia (ADH) and 2 cases of lobular neoplasia (LN). The observed sensitivity and specificity of the cytological imprints for cancer were 100% (one-sided, 97.5% CI: 78.2%–100%). Only one case of ADH could be detected by imprint cytology. Neither of the two LN cases was detected by the imprints. The imprints were uninformative in 11 out of 93 cases (11.8%). There was no uninformative case among women with malignancy.
Conclusion
Imprint cytology provides a rapid, accurate preliminary diagnosis in a few minutes. This method might contribute to the diagnosis of early breast cancer and possibly attenuates patients' anxiety.
doi:10.1186/1477-7819-5-40
PMCID: PMC1876235  PMID: 17407604
7.  US-Guided Vacuum-Assisted Biopsy of Microcalcifications in Breast Lesions and Long-Term Follow-Up Results 
Korean Journal of Radiology  2008;9(6):503-509.
Objective
To evaluate the diagnostic accuracy of the use of an ultrasonography (US)-guided vacuum-assisted biopsy for microcalcifications of breast lesions and to evaluate the efficacy of the use of US-guided vacuum-assisted biopsy with long-term follow-up results.
Materials and Methods
US-guided vacuum-assisted biopsy cases of breast lesions that were performed between 2002 and 2006 for microcalcifications were retrospectively reviewed. A total of 62 breast lesions were identified where further pathological confirmation was obtained or where at least two years of mammography follow-up was obtained. These lesions were divided into the benign and malignant lesions (benign and malignant group) and were divided into underestimated group and not-underestimated lesions (underestimated and not-underestimated group) according to the diagnosis after a vacuum-assisted biopsy. The total number of specimens that contained microcalcifications was analyzed and the total number of microcalcification flecks as depicted on specimen mammography was analyzed to determine if there was any statistical difference between the groups.
Results
There were no false negative cases after more than two years of follow-up. Twenty-nine lesions were diagnosed as malignant (two invasive carcinomas and 27 carcinoma in situ lesions). Two of the 27 carcinoma in situ lesions were upgraded to invasive cancers after surgery. Among three patients diagnosed with atypical ductal hyperplasia, the diagnosis was upgraded to a ductal carcinoma in situ after surgery in one patient. There was no statistically significant difference in the number of specimens with microcalcifications and the total number of microcalcification flecks between the benign group and malignant group of patients and between the underestimated group and not-underestimated group of patients.
Conclusion
US-guided vacuum-assisted biopsy can be an effective alternative to stereotactic-guided vacuum-assisted biopsy in cases where microcalcifications are visible with the use of high-resolution US.
doi:10.3348/kjr.2008.9.6.503
PMCID: PMC2627239  PMID: 19039266
Breast, US; Breast, Biopsy; Breast, Calcification
8.  Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics 
BMC Cancer  2014;14:286.
Background
Mammary microcalcifications have a crucial role in breast cancer detection, but the processes that induce their formation are unknown. Moreover, recent studies have described the occurrence of the epithelial–mesenchymal transition (EMT) in breast cancer, but its role is not defined. In this study, we hypothesized that epithelial cells acquire mesenchymal characteristics and become capable of producing breast microcalcifications.
Methods
Breast sample biopsies with microcalcifications underwent energy dispersive X-ray microanalysis to better define the elemental composition of the microcalcifications. Breast sample biopsies without microcalcifications were used as controls. The ultrastructural phenotype of breast cells near to calcium deposits was also investigated to verify EMT in relation to breast microcalcifications. The mesenchymal phenotype and tissue mineralization were studied by immunostaining for vimentin, BMP-2, β2-microglobulin, β-catenin and osteopontin (OPN).
Results
The complex formation of calcium hydroxyapatite was strictly associated with malignant lesions whereas calcium-oxalate is mainly reported in benign lesions. Notably, for the first time, we observed the presence of magnesium-substituted hydroxyapatite, which was frequently noted in breast cancer but never found in benign lesions. Morphological studies demonstrated that epithelial cells with mesenchymal characteristics were significantly increased in infiltrating carcinomas with microcalcifications and in cells with ultrastructural features typical of osteoblasts close to microcalcifications. These data were strengthened by the rate of cells expressing molecules typically involved during physiological mineralization (i.e. BMP-2, OPN) that discriminated infiltrating carcinomas with microcalcifications from those without microcalcifications.
Conclusions
We found significant differences in the elemental composition of calcifications between benign and malignant lesions. Observations of cell phenotype led us to hypothesize that under specific stimuli, mammary cells, which despite retaining a minimal epithelial phenotype (confirmed by cytokeratin expression), may acquire some mesenchymal characteristics transforming themselves into cells with an osteoblast-like phenotype, and are able to contribute to the production of breast microcalcifications.
doi:10.1186/1471-2407-14-286
PMCID: PMC4021315  PMID: 24758513
9.  Retrieval Rate and Accuracy of Ultrasound-Guided 14-G Semi-Automated Core Needle Biopsy of Breast Microcalcifications 
Korean Journal of Radiology  2014;15(1):12-19.
Objective
To evaluate the retrieval rate and accuracy of ultrasound (US)-guided 14-G semi-automated core needle biopsy (CNB) for microcalcifications in the breast.
Materials and Methods
US-guided 14-G semi-automated CNB procedures and specimen radiography were performed for 33 cases of suspicious microcalcifications apparent on sonography. The accuracy of 14-G semi-automated CNB and radiology-pathology concordance were analyzed and the microcalcification characteristics between groups with successful and failed retrieval were compared.
Results
Thirty lesions were successfully retrieved and the microcalcification retrieval rate was 90.9% (30/33). Thirty lesions were successfully retrieved. Twenty five were finally diagnosed as malignant (10 invasive ductal carcinoma, 15 ductal carcinoma in situ [DCIS]) and five as benign. After surgery and mammographic follow-up, the 25 malignant lesions comprised 12 invasive ductal carcinoma and 13 DCIS. Three lesions in the failed retrieval group (one DCIS and two benign) were finally diagnosed as two DCIS and one benign after surgery. The accuracy of 14-G semi-automated CNB was 90.9% (30/33) because of two DCIS underestimates and one false-negative diagnosis. The discordance rate was significantly higher in the failed retrieval group than in the successful retrieval group (66.7% vs. 6.7%; p < 0.05). Punctate calcifications were significantly more common in the failed retrieval group than in the successful retrieval group (66.7% vs. 3.7%; p < 0.05).
Conclusion
US-guided 14-G semi-automated CNB could be a useful procedure for suspicious microcalcifications in the breast those are apparent on sonography.
doi:10.3348/kjr.2014.15.1.12
PMCID: PMC3909843  PMID: 24497787
Breast biopsy; Breast ultrasound; Breast neoplasms, microcalcifications
10.  Lobular intraepithelial neoplasia arising within breast fibroadenoma 
BMC Research Notes  2013;6:267.
Background
Fibroadenomas are the second most common breast pathology occurring in young women under the age of 35 years old. Fibroadenomas can be classified as simple or complex according to histological features. Complex fibroadenomas differ from simple fibroadenomas because of the presence of cysts (3 mm), sclerosing adenosis, epithelial calcifications, or papillary apocrine changes. Most fibroadenomas are clinically identifiable. In 25% of cases, fibroadenomas are non-palpable and are diagnosed with mammography and ultrasound. Differential diagnosis with well differentiated breast cancer is often necessary, particularly with medullary or mucinous tumors. Calcification findings within fibroadenomas by mammogram have to be investigated. The age of a lump is usually reflected by calcifications. Microcalcification can hide foci of carcinoma in situ when they are small, branching type, and heterogeneous. However, many morphological possibilities may not be reliable for deciding whether a certain calcification is the product of a malignant or a benign process. From a radiological point of view, fibroadenomas containing foci of carcinoma in situ can be indistinguishable from benign lesions, even if the incidence of carcinoma within fibroadenomas is estimated as 0.1–0.3%, and it could be a long-term risk factor for invasive breast cancer.
Case presentation
A 44-year-old woman presented with a 1.5-cm palpable, smooth, mobile lump in the lower-inner quadrant of her right breast. Standard mediolateral oblique and craniocaudal mammograms showed a cluster of eccentric popcorn-like calcifications within the fibroadenoma. After lumpectomy, a definitive histological examination confirmed the intra-operative diagnosis of a benign mass. However, lobular intraepithelial neoplasia foci were found, surrounded by atypical lobular hyperplasia.
Conclusions
The possibility of an old benign breast lump might be supported by fine needle aspiration biopsy or core biopsy before initiating follow-up. According to our experience, when patients are older than 40 years and have a familial history of breast cancer, we prefer to carry out lumpectomy with follow up to avoid the risk of underestimation in situ foci within the lump.
doi:10.1186/1756-0500-6-267
PMCID: PMC3716517  PMID: 23849288
Fibroadenoma; Lobular intraepithelial neoplasia; Popcorn-like calcifications
11.  Serum calcium levels, TRPM7, TRPC1, microcalcifications, and breast cancer using breast imaging reporting and data system scores 
Background
An association between higher serum calcium (Ca2+) levels and breast cancer has been previously reported. However, little is known regarding the relationship between serum Ca2+ levels and the expression of Ca2+ channels in the presence of breast microcalcifications.
Methods
A retrospective analysis of women newly diagnosed with breast microcalcifications was performed based on the Breast Imaging Reporting and Data System (BI-RADS). The expression of TRPC1, TRPC3, and TRPM7 using normal biopsy without microcalcifications (controls) and infiltrating ductal carcinoma with microcalcifications was evaluated.
Results
Data on 138 women were analyzed. Seventy percent of women had a BI-RADS score (1–3) corresponding to benign disease. Seventy-six percent of women with a BI-RADS score (4 or 5) were diagnosed with breast cancer, 56% were cancers in situ, and 93% were infiltrating ductal carcinomas. No difference in the distribution of corrected serum Ca2+ levels between BI-RADS scores (1–3) and BI-RADS scores (4–5) (P = 0.82) was observed. Serum Ca2+ levels were similar in women without cancer and women diagnosed with breast cancer (P = 0.94). However, the expression of TRPM7 and TRPC1, but not TRPC3, Ca2+ channels were increased in infiltrating ductal carcinoma samples with microcalcifications when compared with age-matched controls without calcification or cancer.
Conclusion
We observed an increase in the expression of TRPM7 and TRPC1 Ca2+ channels in infiltrating ductal carcinoma samples with microcalcifications, whereas no change in serum Ca2+ levels was observed. Together these data suggest that increased expression of these channels might lead to an increase in intracellular Ca2+ levels thereby restoring serum Ca2+ levels, but these can contribute to the breast microcalcifications. However, future studies exploring the intracellular Ca2+ levels as well as the role of TRPM7 and TRPC1 function according to BI-RADS scores are needed.
doi:10.2147/BCTT.S37436
PMCID: PMC3644982  PMID: 23662076
breast microcalcifications; BI-RADS; Ca2+; ductal carcinoma; TRPC1; TRPM7
12.  Serum calcium levels, TRPM7, TRPC1, microcalcifications, and breast cancer using breast imaging reporting and data system scores 
Background
An association between higher serum calcium (Ca2+) levels and breast cancer has been previously reported. However, little is known regarding the relationship between serum Ca2+ levels and the expression of Ca2+ channels in the presence of breast microcalcifications.
Methods
A retrospective analysis of women newly diagnosed with breast microcalcifications was performed based on the Breast Imaging Reporting and Data System (BI-RADS). The expression of TRPC1, TRPC3, and TRPM7 using normal biopsy without microcalcifications (controls) and infiltrating ductal carcinoma with microcalcifications was evaluated.
Results
Data on 138 women were analyzed. Seventy percent of women had a BI-RADS score (1–3) corresponding to benign disease. Seventy-six percent of women with a BI-RADS score (4 or 5) were diagnosed with breast cancer, 56% were cancers in situ, and 93% were infiltrating ductal carcinomas. No difference in the distribution of corrected serum Ca2+ levels between BI-RADS scores (1–3) and BI-RADS scores (4–5) (P = 0.82) was observed. Serum Ca2+ levels were similar in women without cancer and women diagnosed with breast cancer (P = 0.94). However, the expression of TRPM7 and TRPC1, but not TRPC3, Ca2+ channels were increased in infiltrating ductal carcinoma samples with microcalcifications when compared with age-matched controls without calcification or cancer.
Conclusion
We observed an increase in the expression of TRPM7 and TRPC1 Ca2+ channels in infiltrating ductal carcinoma samples with microcalcifications, whereas no change in serum Ca2+ levels was observed. Together these data suggest that increased expression of these channels might lead to an increase in intracellular Ca2+ levels thereby restoring serum Ca2+ levels, but these can contribute to the breast microcalcifications. However, future studies exploring the intracellular Ca2+ levels as well as the role of TRPM7 and TRPC1 function according to BI-RADS scores are needed.
doi:10.2147/BCTT.S37436
PMCID: PMC3644982  PMID: 23662076
breast microcalcifications; BI-RADS; Ca2+; ductal carcinoma; TRPC1; TRPM7
13.  Fuzzy technique for microcalcifications clustering in digital mammograms 
BMC Medical Imaging  2014;14:23.
Background
Mammography has established itself as the most efficient technique for the identification of the pathological breast lesions. Among the various types of lesions, microcalcifications are the most difficult to identify since they are quite small (0.1-1.0 mm) and often poorly contrasted against an images background. Within this context, the Computer Aided Detection (CAD) systems could turn out to be very useful in breast cancer control.
Methods
In this paper we present a potentially powerful microcalcifications cluster enhancement method applicable to digital mammograms. The segmentation phase employs a form filter, obtained from LoG filter, to overcome the dependence from target dimensions and to optimize the recognition efficiency. A clustering method, based on a Fuzzy C-means (FCM), has been developed. The described method, Fuzzy C-means with Features (FCM-WF), was tested on simulated clusters of microcalcifications, implying that the location of the cluster within the breast and the exact number of microcalcifications are known.
The proposed method has been also tested on a set of images from the mini-Mammographic database provided by Mammographic Image Analysis Society (MIAS) publicly available.
Results
The comparison between FCM-WF and standard FCM algorithms, applied on both databases, shows that the former produces better microcalcifications associations for clustering than the latter: with respect to the private and the public database we had a performance improvement of 10% and 5% with regard to the Merit Figure and a 22% and a 10% of reduction of false positives potentially identified in the images, both to the benefit of the FCM-WF. The method was also evaluated in terms of Sensitivity (93% and 82%), Accuracy (95% and 94%), FP/image (4% for both database) and Precision (62% and 65%).
Conclusions
Thanks to the private database and to the informations contained in it regarding every single microcalcification, we tested the developed clustering method with great accuracy. In particular we verified that 70% of the injected clusters of the private database remained unaffected if the reconstruction is performed with the FCM-WF. Testing the method on the MIAS databases allowed also to verify the segmentation properties of the algorithm, showing that 80% of pathological clusters remained unaffected.
doi:10.1186/1471-2342-14-23
PMCID: PMC4105893  PMID: 24961885
Breast cancer; Microcalcifications; Spatial filters; Clustering; Fuzzy logic; C-means; Mammography; Segmentation
14.  A method for detecting microcalcifications in Digital Mammograms 
Journal of Digital Imaging  1997;10(Suppl 1):136-139.
Microcalcification clusters are often an important indicator for the detection of malignancy in mammograms. In many cases, microcalcifications are the only indication of a malignancy. However, the detection of microcalcifications can be a difficult process. They are small and can be embedded in dense tissue. This paper presents a method for automatically detecting microcalcifications. We utilize a high-boost filter to suppress background clutter enabling segmentation even in very dense breast tissue. We then use a threshholding and region growing technique to extract candidate microcalcifications. Likely microcalcifications are then identified by a linear classifier. We apply this method to images selected from the LLNL/UCSF Digital Mammogram Library, and produce a receiver operating characteristic (ROC) curves to detail the trade-off between probability of detection and false alarms. Finally, we exam the ability to properly select a threshold to achieve a desired probability of detection based upon a training set.
doi:10.1007/BF03168677
PMCID: PMC3452798  PMID: 9268859
digital mammography; microcalcifications; high-boost filtering; detection
15.  Pathologic Complete Response of HER-2 Neu-Positive Invasive Ductal Carcinoma and Ductal Carcinoma In Situ following Neoadjuvant Chemotherapy plus Trastuzumab: A Case Report and Review of Literature 
Case Reports in Surgery  2012;2012:454273.
Pathologic complete response (pCR) after NC has been consistently associated with improved outcomes. Residual DCIS after NC does not portray worse prognosis compared to complete eradication of all disease but has clinical implications regarding surgical management. We report a case of pCR of DCIS associated with invasive carcinoma in an HER-2 + tumor after NC plus trastuzumab despite persistence of malignant-appearing microcalcifications mammographically. A 41-year-old Caucasian female presented with a 4 × 4 cm mass in the right breast and a 2.5 cm right axillary node. Mammogram showed a 2.5 cm mass and a 12 cm area of linear pleomorphic, suspicious calcifications in the upper part of the breast. Core biopsy revealed invasive ductal carcinoma and DCIS associated with calcifications (ER 85%, PR 6%, Her2neu 3+ by IHC). Axillary node FNA was positive for malignancy. The patient received doxorubicin/cyclophosphamide (AC) → paclitaxel plus T with complete clinical and radiologic response but no significant change in the microcalcifications. Final pathology showed no residual invasive carcinoma or DCIS despite the presence of numerous ducts with microcalcifications. Documented eradication of DCIS has not been reported following NC when malignant-appearing calcifications persist and this observation may have important clinical implications regarding surgical management.
doi:10.1155/2012/454273
PMCID: PMC3350088  PMID: 22606601
16.  Absence of Residual Microcalcifications in Atypical Ductal Hyperplasia Diagnosed via Stereotactic Vacuum-Assisted Breast Biopsy: Is Surgical Excision Obviated? 
Journal of Breast Cancer  2014;17(3):265-269.
Purpose
The purpose of our study was to evaluate the underestimation rate of atypical ductal hyperplasia (ADH) on vacuum-assisted breast biopsy (VABB), and to examine the correlation between residual microcalcifications and the underestimation rate of ADH.
Methods
A retrospective study was performed on 27 women (mean age, 49.2±9.2 years) who underwent additional excision for ADH via VABB for microcalcifications observed by using mammography. The mammographic findings, histopathologic diagnosis of all VABB and surgical specimens, and association of malignancy with residual microcalcifications were evaluated. The underestimation rate of ADH was also calculated.
Results
Of the 27 women with microcalcifications, nine were upgraded to ductal carcinoma in situ (DCIS); thus, the underestimation rate was 33.3% (9/27). There was no difference in age (p=0.40) and extent of microcalcifications (p=0.10) when comparing benign and malignant cases. Six of 17 patients (35.3%) with remaining calcifications after VABB were upgraded to DCIS, and three of 10 patients (30%) with no residual calcifications after VABB were upgraded (p=1.00).
Conclusion
The underestimation rate of ADH on VABB was 33.3%. Furthermore, 30% of patients with no remaining calcifications were upgraded to DCIS. Therefore, we conclude that all ADH cases diagnosed via VABB should be excised regardless of the presence of residual microcalcifications.
doi:10.4048/jbc.2014.17.3.265
PMCID: PMC4197357  PMID: 25320625
Breast; Calcinosis; Large-core needle biopsy; Mammography; Segmental mastectomy
17.  Joint two-view information for computerized detection of microcalcifications on mammograms 
Medical physics  2006;33(7):2574-2585.
We are developing new techniques to improve the accuracy of computerized microcalcification detection by using the joint two-view information on craniocaudal (CC) and mediolateral-oblique (MLO) views. After cluster candidates were detected using a single-view detection technique, candidates on CC and MLO views were paired using their radial distances from the nipple. Candidate pairs were classified with a similarity classifier that used the joint information from both views. Each cluster candidate was also characterized by its single-view features. The outputs of the similarity classifier and the single-view classifier were fused and the cluster candidate was classified as a true microcalcification cluster or a false-positive (FP) using the fused two-view information. A data set of 116 pairs of mammograms containing microcalcification clusters and 203 pairs of normal images from the University of South Florida (USF) public database was used for training the two-view detection algorithm. The trained method was tested on an independent test set of 167 pairs of mammograms, which contained 71 normal pairs and 96 pairs with microcalcification clusters collected at the University of Michigan (UM). The similarity classifier had a very low FP rate for the test set at low and medium levels of sensitivity. However, the highest mammogram-based sensitivity that could be reached by the similarity classifier was 69%. The single-view classifier had a higher FP rate compared to the similarity classifier, but it could reach a maximum mammogram-based sensitivity of 93%. The fusion method combined the scores of these two classifiers so that the number of FPs was substantially reduced at relatively low and medium sensitivities, and a relatively high maximum sensitivity was maintained. For the malignant microcalcification clusters, at a mammogram-based sensitivity of 80%, the FP rates were 0.18 and 0.35 with the two-view fusion and single-view detection methods, respectively. When the training and test sets were switched, a similar improvement was obtained, except that both the fusion and single-view detection methods had superior test performances on the USF data set than those on the UM data set. Our results indicate that correspondence of cluster candidates on two different views provides valuable additional information for distinguishing FPs from true microcalcification clusters.
PMCID: PMC3026322  PMID: 16898462
computer-aided diagnosis; microcalcification clusters; segmentation
18.  Usefulness of Texture Analysis for Computerized Classification of Breast Lesions on Mammograms 
Journal of Digital Imaging  2006;20(3):248-255.
This work presents the usefulness of texture features in the classification of breast lesions in 5518 images of regions of interest, which were obtained from the Digital Database for Screening Mammography that included microcalcifications, masses, and normal cases. Sixteen texture features were used, i.e., 13 were based on the spatial gray-level dependence matrix and 3 on the wavelet transform. The nonparametric K-NN classifier was used in the classification stage. The results obtained from receiver operating characteristic analysis indicated that the texture features can be used for separating normal regions and lesions with masses and microcalcifications, yielding the area under the curve (AUC) values of 0.957 and 0.859, respectively. However, the texture features were not very effective for distinguishing between malignant and benign lesions because the AUC was 0.617 for masses and 0.607 for microcalcifications. The study showed that the texture features can be used for the detection of suspicious regions in mammograms.
doi:10.1007/s10278-006-9945-8
PMCID: PMC3043897  PMID: 17122993
Mammography; computer-aided diagnosis; texture analysis
19.  Bayesian Classifier with Simplified Learning Phase for Detecting Microcalcifications in Digital Mammograms 
Detection of clustered microcalcifications (MCs) in mammograms represents a significant step towards successful detection of breast cancer since their existence is one of the early signs of cancer. In this paper, a new framework that integrates Bayesian classifier and a pattern synthesizing scheme for detecting microcalcification clusters is proposed. This proposed work extracts textural, spectral, and statistical features of each input mammogram and generates models of real MCs to be used as training samples through a simplified learning phase of the Bayesian classifier. Followed by an estimation of the classifier's decision function parameters, a mammogram is segmented into the identified targets (MCs) against background (healthy tissue). The proposed algorithm has been tested using 23 mammograms from the mini-MIAS database. Experimental results achieved MCs detection with average true positive (sensitivity) and false positive (specificity) of 91.3% and 98.6%, respectively. Results also indicate that the modeling of the real MCs plays a significant role in the performance of the classifier and thus should be given further investigation.
doi:10.1155/2009/767805
PMCID: PMC2810460  PMID: 20119490
20.  Fine-needle aspiration cytology of extra mammary metastatic lesions in the breast: A retrospective study of 36 cases diagnosed during 18 years 
CytoJournal  2010;7:10.
Background:
Metastatic tumors in the breast require treatment according to origin and type of tumor. It is important to recognize these lesions in fine-needle aspiration cytology (FNAC) in order to avoid unnecessary mastectomy or non-relevant chemotherapy. The aim of this study was to evaluate the cytological features of metastatic tumors and possible criteria that could alert us as to the possibility of a metastasis from an extra mammary malignancy.
Methods:
The material included 36 confirmed or suspected metastases in the breast registered in the pathology files at Oslo University Hospital, Ulleval, during 1990–2007. There were a total of 6,325 cases of malignant breast FNAC, representing 30 men and 6,295 women. Smears were evaluated for the amount of material, presence or absence of myoepithelial cells, microcalcifications, mitoses and necrotic material. All carcinomas were graded.
Results:
There were seven men (7/30 = 23.3%) and 29 women (29/6,295 = 0.46%). The primary tumor was known in 22 cases (22/36 = 61.1%). No other primary tumor was known and metastatic lesion was not initially suspected in 14 cases (14/36 = 38.9%). The most common origin was lung (15/36 = 41.7%). In five cases (5/36 = 13.9%), the origin remained uncertain.
Conclusions:
Metastases from extra mammary sites are (relatively) common in males (23.3%). In women, metastatic lesions are rare (0.46%). A large proportion of them (88%) are high-grade adenocarcinomas and poorly differentiated carcinomas that may resemble grade 3 ductal carcinomas. Unusual clinical and/or radiological presentation in combination with high-grade malignant cells should alert us to consider the possibility of a metastasis.
doi:10.4103/1742-6413.65056
PMCID: PMC2924528  PMID: 20806071
Breast; cytological features; extra mammary; FNAC; grade; metastases
21.  CAD May Not be Necessary for Microcalcifications in the Digital era, CAD May Benefit Radiologists for Masses 
Objective:
The aim of this study was to evaluate the effectiveness of computer-aided detection (CAD) to mark the cancer on digital mammograms at the time of breast cancer diagnosis and also review retrospectively whether CAD marked the cancer if visible on any available prior mammograms, thus potentially identifying breast cancer at an earlier stage. We sought to determine why breast lesions may or may not be marked by CAD. In particular, we analyzed factors such as breast density, mammographic views, and lesion characteristics.
Materials and Methods:
Retrospective review from 2004 to 2008 revealed 3445 diagnosed breast cancers in both symptomatic and asymptomatic patients; 1293 of these were imaged with full field digital mammography (FFDM). After cancer diagnosis, in a retrospective review held by the radiologist staff, 43 of these cancers were found to be visible on prior-year mammograms (false-negative cases); these breast cancer cases are the basis of this analysis. All cases had CAD evaluation available at the time of cancer diagnosis and on prior mammography studies. Data collected included patient demographics, breast density, palpability, lesion type, mammographic size, CAD marks on current- and prior-year mammograms, needle biopsy method, pathology results (core needle and/or surgical), surgery type, and lesion size.
Results:
On retrospective review of the mammograms by the staff radiologists, 43 cancers were discovered to be visible on prior-year mammograms. All 43 cancers were masses (mass classification included mass, mass with calcification, and mass with architectural distortion); no pure microcalcifications were identified in this cohort. Mammograms with CAD applied at the time of breast cancer diagnosis were able to detect 79% (34/43) of the cases and 56% (24/43) from mammograms with CAD applied during prior year(s). In heterogeneously dense/extremely dense tissue, CAD marked 79% (27/34) on mammograms taken at the time of diagnosis and 56% (19/34) on mammograms with CAD applied during the prior year(s). At time of diagnosis, CAD marked lesions in 32% (11/34) on the craniocaudal (CC) view, 21% (7/34) on the mediolateral oblique (MLO) view. Lesion size of those marked by CAD or not marked were similar, the average being 15 and 12 mm, respectively.
Conclusion:
CAD marked cancers on mammograms at the time of diagnosis in 79% of the cases and in 56% of the cases from the mammograms with CAD applied in the prior year(s). Our review demonstrated that CAD can mark invasive breast carcinomas in even dense breast tissue. CAD marked a significant portion on the CC view only, which may be an indicator to radiologists to be especially vigilant when a lesion is marked on this view.
doi:10.4103/2156-7514.99179
PMCID: PMC3424776  PMID: 22919559
Breast carcinoma; breast imaging; calcifications; computer-aided detection; digital mammography
22.  Ultrasound and Clinicopathological Characteristics of Triple Receptor-Negative Breast Cancers 
Journal of Breast Cancer  2011;14(2):119-123.
Purpose
Triple receptor-negative (TRN) breast cancer is associated with high risk of recurrence and poor prognosis. The present study assessed the clinicopathologic characteristics and ultrasound (US) features of TRN breast cancers.
Methods
Pathological and biological data were reviewed for 558 breast cancer patients treated at Kangbuk Samsung Hospital, between January 2003 and December 2009. The patients were separated into TRN breast cancer and non-TRN breast cancer groups, based on the results of immunohistochemical prognostic panels. Clinical and pathologic features were compared for the two groups. US features, including shape, orientation, margins, boundaries, echo patterns, posterior acoustic features, surrounding tissues, and microcalcifications, were determined for 41 TRN patients and 189 non-TRN controls (ER+/PR+/HER2-).
Results
Of 558 cases, 58 (10.4%) had the TRN phenotype. Four hundred and thirty-four cases (77.8%) were invasive ductal carcinomas. TRN cancer was significantly associated with specific characteristics of tumor size, nuclear grade, histologic grade, venous invasion, and lymphatic invasion. With respect to US features, TRN cancers were more likely to have an oval shape, a circumscribed margin, and marked hypoechogenicity.
Conclusion
Tumor characteristics were different between TRN and non-TRN breast cancers, although US cannot differentiate the subtype of breast cancers TRN cancer tend to show somewhat different US morphology.
doi:10.4048/jbc.2011.14.2.119
PMCID: PMC3148546  PMID: 21847406
Breast neoplasms; Hormone receptor; Pathology; Ultrasouography
23.  A Comparative Study of the Diagnostic Value of Contrast-Enhanced Breast MR Imaging and Mammography on Patients with BI-RADS 3–5 Microcalcifications 
PLoS ONE  2014;9(11):e111217.
Objective
To retrospectively investigate the diagnostic value of breast MRI in patients with BI-RADS 3–5 microcalcifications in mammography.
Methods
Eighty-four patients with BI-RADS 3–5 microcalcifications on mammography underwent breast MR exams before surgical biopsy with a hookwire position under mammographic guidance. Two radiologists reviewed each lesion with BI-RADS by consensus. The diagnostic value of mammography and MRI was compared.
Results
Histopathological examination revealed 49 benign lesions and 42 malignant lesions. In the assessments of mammography, 21 lesions (23.1%) were assigned to category 3, 51 lesions (56.0%) to category 4, and 19 lesions (20.9%) to category 5. The area under the receiver operating characteristic(ROC) curve for mammography and MR assessment was 0.844, and 0.945, respectively (p<0.05). In cases of category 3 microcalcifications, the specificity of mammography and MR was 100%, and 95.2% (p = 1.000), respectively. In cases of category 4 microcalcifications, the specificity, PPV and accuracy of mammography was 0%, 45.1% and 45.1%; whereas those for MR was 82.1% (p<0.05), 80.8% (P = 0.003) and 86.3% (p<0.05). All microcalcifications of category 5 were correctly diagnosed by mammography and MR.
Conclusions
Breast MRI has the potential to significantly improve the diagnosis of category 4 microcalcifications on mammography. Among mammographic category 4 microcalcifications, about 82% of benign lesions can be degraded to BI-RADS 1∼3 by MRI. However for microcalcifications of category 3 and 5, MR exams do not show significant improvement over mammography.
doi:10.1371/journal.pone.0111217
PMCID: PMC4218847  PMID: 25365327
24.  Proposed algorithm for management of patients with thyroid nodules/focal lesions, based on ultrasound (US) and fine-needle aspiration biopsy (FNAB); our own experience 
Thyroid Research  2013;6:6.
Background
The standard management in patients with thyroid nodules is to assess the risk of malignancy, based on cytological examination. On the other hand, there are thyroid patterns of ultrasound (US) image, associated with an increased risk of malignancy.
The aim of our study was to create a diagnostic algorithm that would employ both data from US examination (expressed by a total score, according to our scoring system) and FNAB results, classified according to Bethesda system (The Bethesda System for Reporting Thyroid Cytopathology - TBSRTC categories).
Material and methods
100 thyroid cancer foci (94 papillary carcinomas, 4 medullary carcinomas, 2 undifferentiated carcinomas) and 100 benign focal lesions were selected during postoperative histopathological examination of thyroid glands excised during surgery from 111 patients. The corresponding US images of each lesion – performed in the course of preoperative diagnostics – were evaluated for the presence of seven (7) different features in US image, suggesting a malignant character of lesion, viz. vascularity, i.e., the increased central intranodular blood flows, microcalcifications, “taller-than-wide” orientation, solid composition, hypoechogenicity, irregular margin and either absence of peripheral halo or the presence of outer shell of uneven thickness, surrounding the lesion. The sensitivity, specificity, positive predictive values, negative predictive values and odds ratios for each US feature were calculated.
Results
In US image of the analyzed cancer foci, we obtained the following values of odds ratio for each of the above mentioned features suggesting malignancy: “taller-than-wide” orientation - odds ratio - 301.0, microcalcifications - 24.67, increased intranodular vascularity - 20.44, hypoechogenicity - 18.61, irregular margins - 7.81, absence of halo - 5.88, and solid composition - 4.16.
Taking into account our own experience and the present data, in juxtaposition with the opinions of other authors, we propose a division of US features into 3 groups of different prognostic importance, expressed by a total score calculated based on our scoring system. Accordingly, microcalcifications, “taller-than-wide” orientation, the increased intranodular vascularity, and hypoechogenicity constitute one group - each of the features in this group is awarded 1 point. In turn, the characteristics of minor prognostic importance, such as irregular margin, absence of halo, solid composition, and large size (a diameter longer than 3.0 cm) - are associated with the granting 0.5 points each. The most important prognostic features – a rapid growth (enlargement) of nodules/focal lesions and a presence of pathologically altered lymph nodes are associated with the granting 3 points for each.
Our scoring system can be applied in order to better assessment of thyroid US patterns in whole. In patients with a total score ranging from 0 < 4 points there is US pattern of a low risk of malignancy, with ≥ 4 < 7 points - intermediate risk, and in patients with a score ≥ 7 points – a high risk in question.
Conclusion
Complementary use of our scoring system and FNAB TBSRTC categories can help to make optimal clinical decisions as regards the selection of treatment strategy.
doi:10.1186/1756-6614-6-6
PMCID: PMC3668175  PMID: 23601166
25.  Patient-calibrated agent-based modelling of ductal carcinoma in situ (DCIS): From microscopic measurements to macroscopic predictions of clinical progression 
Journal of Theoretical Biology  2012;301:122-140.
Ductal carcinoma in situ (DCIS)—a significant precursor to invasive breast cancer—is typically diagnosed as microcalcifications in mammograms. However, the effective use of mammograms and other patient data to plan treatment has been restricted by our limited understanding of DCIS growth and calcification. We develop a mechanistic, agent-based cell model and apply it to DCIS. Cell motion is determined by a balance of biomechanical forces. We use potential functions to model interactions with the basement membrane and amongst cells of unequal size and phenotype. Each cell’s phenotype is determined by genomic/proteomic- and microenvironment-dependent stochastic processes. Detailed “sub-models” describe cell volume changes during proliferation and necrosis; we are the first to account for cell calcification.
We introduce the first patient-specific calibration method to fully constrain the model based upon clinically-accessible histopathology data. After simulating 45 days of solid-type DCIS with comedonecrosis, the model predicts: necrotic cell lysis acts as a biomechanical stress relief, and is responsible for the linear DCIS growth observed in mammography; the rate of DCIS advance varies with the duct radius; the tumour grows 7 to 10 mm per year—consistent with mammographic data; and the mammographic and (post-operative) pathologic sizes are linearly correlated—in quantitative agreement with the clinical literature. Patient histopathology matches the predicted DCIS microstructure: an outer proliferative rim surrounds a stratified necrotic core with nuclear debris on its outer edge and calcification in the centre. This work illustrates that computational modelling can provide new insight on the biophysical underpinnings of cancer. It may one day be possible to augment a patient’s mammography and other imaging with rigorously-calibrated models that help select optimal surgical margins based upon the patient’s histopathologic data.
doi:10.1016/j.jtbi.2012.02.002
PMCID: PMC3322268  PMID: 22342935
agent-based model; tumour simulation; comedonecrosis; DCIS; ductal carcinoma in situ; biomechanics; calcification; patient-specific calibration

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