Original Article

Yonago Acta medica 2015;58:89–93

Clinical Significance of Microcalcifications Detection in Invasive Breast Carcinoma
Yuki Hashimoto,* Aya Murata,* Naoki Miyamoto,* Toshihiro Takamori,* Yuta Hosoda,* Yukari Endo,* Yuka Kodani,*Kengo Sato,* Keiko Hosoya,† Kiyosuke Ishiguro† and Yasuaki Hirooka**Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine,
Yonago 683-8503, Japan and †Division of Breast and Endocrine Surgery, Tottori University Hospital, Yonago 683-8504, Japan

ABSTRACT

Key words breast carcinoma; microcalcification; ultra-

Backgroundsonography

Recently, a lot of cases with microcalcifications of the breast are pointed by the images ofmammography (MG), because breast screening using
MG become common. Although MG is a gold standard
modality for detecting microcalcifications, images ofultrasonography (US) are now feasible to detect microcalcifications with recent improvements to ultrasounddiagnostic devices. In this report, we analyzed clinicalsignificance of microcalcifications detected with US images in invasive breast carcinoma.
Methods Eighty-eight patients with invasive breast
carcinoma who underwent MG and US before surgery at
the Division of Breast and Endocrine Surgery of Tottori
University Hospital between January 2012 and August 2013. After reviewing US images, the association
between the presence of echogenic spots that indicate
microcalcifications and images of MG or pathologicalfindings was assessed.
Results Patients without microcalcifications on US
images were significantly more likely to have the Luminal A subtype and a lower nuclear grading. Conversely,
patients with microcalcifications on US images weresignificantly more likely to have higher level of MIB1 index, lymphovascular invasion, comedonecrosis andlymph node metastasis. The rate of detecting microcalcifications on US images was relatively good, with 81.8%
of sensitivity, 94.5% of specificity and 89.8% of diagnostic accuracy. Among the calcifications detected by MG
images, detected rate of calcifications with US images
was higher in necrotic type (92.6%) than secretory type(33.3%).
Conclusion This study suggest that microcalcifications of tumors detected by US images could serve as an
useful prediction to evaluate the degree of malignancy
for patients with invasive breast carcinoma.

Recently, a lot of cases with microcalcifications of thebreast are pointed by the images of mammography (MG),because breast screening using MG become common.
Although MG is a gold standard modality for detecting
microcalcifications, images of ultrasonography (US) are
now feasible to detect microcalcifications with recent
improvements to ultrasound diagnostic devices.1-4 There
have been several studies on the performance of US for
detecting microcalcifications, but most reports focusedon ductal carcinoma in situ (DCIS).1–3, 5 Microcalcifications are seen in invasive carcinomas as well as DCIS
(Fig. 1), but there have been few detailed studies about
the significance of microcalcifications in such carcinomas. In this study, we compared the presence of microcalcifications on US images with findings from MG images and clinical pathology, to interpret the significanceof detection of microcalcifications on US images.
SUBJECTS AND METHODSPatients

Eighty-eight patients with invasive breast carcinoma
who underwent preoperative MG and US in the Divisionof Breast and Endocrine Surgery of Tottori University
Hospital between January 2012 and August 2013 wereretrospectively investigated. Patients with DCIS andthose who received neoadjuvant chemotherapy were excluded.
Methods

US examinations were performed using a HI VISION
Preirus (Hitachi Aloka Medical, Tokyo, Japan) with an
EUP-L74M probe (linear, center frequency: 7.5 MHz).
Echogenic spots indicative of microcalcifications were
defined as discontinuous echogenic spots within a massor hypoechoic area, or clustered echogenic spots clearly
different from the mammary glands (Fig. 2). In thisstudy, we defined microcalcifications detected by MG
images as positive cases of microcalcifications. Preoperative MG and US images were retrospectively reviewed
individually without patients information by a medical

Corresponding author: Yasuaki Hirooka, MD, PhD
yhirooka@med.tottori-u.ac.jp
Received 2015 March 25
Accepted 2015 April 27
Abbreviations: DCIS, ductal carcinoma in situ; HER2, human epidermal growth factor receptor 2; MG, mammography; US, ultrasonography89

Y. Hashimoto
Fig. 1 et al.

Fig. 2-A

Fig. 1. US images show microcalcifications (arrows) observed not only in DCIS (left) but also in invasive carcinoma (right). DCIS, ductal carcinoma in situ; US, ultrasonography.

A

Fig. 2-B
B

Fig. 2. Microcalcifications on US images.
A: Transverse (left) and longitudinal (right) US
images of the AC area of the left breast. Noncontinuous echogenic spots (arrows) were observedon orthogonal tomographic images.
B: Longitudinal image of the C area of the left
breast. Punctuate echogenic spots (arrows) with atissue composition clearly different from that of
the mammary glands were observed inside themass.
US, ultrasonography.

RESULTS
All patients were female and mean age was 61.2 years(range: 28–87 years). Table 1 shows the results of relationship between US and MG images for detecting
microcalcifications in all 88 patients. Microcalcifications
were detected in 33 patients but not in 55 patients with
MG images. Twenty-seven of the 33 patients appeared asechogenic spots on US images. US examination showed
81.8% sensitivity, 94.5% specificity and 89.8% diagnostic accuracy for detecting microcalcifications. There
were 6 false negatives where microcalcifications weredetected with MG but not US images. Conversely, there
were 3 false positives where microcalcifications were
not detected with MG but echogenic spots were seen
on US images. In such false positive cases, pathological
specimens revealed no microcalcifications and no characteristic features.

breast cancer specialist who had over 25 years experiences in breast examinations and a medical sonographer(superficial organs) with over 3 years experiences. Whenmutual evaluation of findings was not matched, consensuses were got in each other. The association between
the presence of echogenic spots within a tumor on US
images and findings from MG images and pathologicalfeatures of the resected specimen (subtype, histologic
type, lymphovascular invasion, comedonecrosis, nuclear
grading, MIB-1 index and lymph node metastases) were
investigated. Fischer’s exact test and the Mann-Whitney
U test were used for statistical analysis. P values of lessthan 0.05 were considered to indicate statistically significant differences. This study was conducted with theapproval of the Ethics Committee of Tottori University
Faculty of Medicine.
90Microcalcification in breast carcinoma

showed 92.6% sensitivity, 66.7% specificity for detecting
necrotic calcifications. In six false negative cases, 4 hadsecretary types and 2 had necrotic types.
Table 3 shows a correlation between the presence of
microcalcifications and clinicopathological findings in
79 patients, with the 3 false positives and 6 false negatives excluded. Patients without microcalcifications weresignificantly more likely to have the Luminal A subtype(P < 0.01) and a lower nuclear grading (P < 0.05). Conversely, patients with microcalcifications were significantly more likely to have lymphatic invasion (P < 0.05),
comedonecrosis (P < 0.01), more lymph node metastases(P < 0.01) and higher level of MIB-1 index (34.8% vs.
22.0%; P < 0.01) (Fig. 3). Histologic type and vascularinvasion were not associated with the presence of microcalcifications.

Table 1. Detection of microcalcifications with MG and
US
MG
Total
+
−
+
30
27
3
US
6
52
−
58
Total
33
55
88
US examination showed 81.8% sensitivity, 94.5% specificity and89.8% diagnostic accuracy for detecting microcalcifications.
MG, mammography; US, ultrasonography.

US detectivity for microcalcifications was evaluated(Table 2). It was found that US examination detected ahigher rate of pleomorphic or linear/branching calcifications that appeared to be necrotic calcifications (25/27)
compared with amorphous calcifications that appeared
to be secretory calcifications (2/6). And US examination

Table 2. US detectivity for microcalcifications
Type of microcaplcification with MG
Necrotic (pleomorphic or linear/branching)
Secretory (amorphous)
+
25
2
US
2
4
−

P value< 0.01

US examination showed 92.6% sensitivity, 66.7% specificity for detecting necrotic calcifications.
MG, mammography; US, ultrasonography.
Table 3. Microcalcifications and pathological findings

SubtypeHistological classification
Lymphatic invasion
Vascular invasion
Comedonecrosis
Nuclear atypia
Number of mitotic counts
Nuclear grading
Lymph node metastases

Microcalcification+−(n = 27)(n = 52)
0
17
19
25
3
2
2
3
3
5
8
20
7
8
11
14
1
10
16
15
11
36
2
1
25
50
21
17
5
33
1
11
20
20
5
11
3
19
13
16
10
7
3
19
11
10
12
13
14
8
13
44

Luminal A
Luminal B(HER2−)
Luminal B(HER2+)
HER2 enriched
Triple negative
Scirrhous carcinoma
Solid-tubular carcinoma
Papillotubular carcinoma
Special types
+
−
+
−
+
−
1
2
3
1
2
3
1
2
3
+
−

HER2, human epidermal growth factor receptor 2; NS, not significant.

91

P value< 0.01NS< 0.05NS< 0.01< 0.05< 0.05< 0.05< 0.01

回査読図表修正済（2015.6.15）.pdf 1 2015/06/29 16:47

Y. Hashimoto et al.
100
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receptor 2 (HER2) is associated with microcalcifications, but there is no association in our study. The reason
for this may be the different rate of patients with HER2
overexpression. Seo et al.13 reported approximately 30%
of all patients with HER2 overexpression, whereas ourstudy included a small number of patients (13%).
In contrast, patients with microcalcifications on US
images were significantly more likely to have lymphatic
invasion, comedonecrosis, more lymph node metastases
and higher level of MIB-1 index. Previous studies haveshown that lymphovascular invasion,14 comedonecrosis15
and MIB-1 index16 could be useful prognostic factors of
the patients with breast carcinoma. Additionally, axillary
lymph node metastasis is a major prognostic factor andplay an important role in selecting adjuvant therapy.17–19
As described above, lymphatic invasion, comedonecrosis, lymph node metastases and higher level of MIB-1** P<0.01
index are considered indicators of high grade malignancy and poor prognosis. These findings suggest thatbreast carcinoma with microcalcifications may be highgrade malignant and the patients with them have an unfavorable prognosis.
The results of US images for detecting microcalcifications in this study were inferior to those of MG
images, but still relatively good of sensitivity, specificity
and diagnostic accuracy. Calcifications of the breast canbe conceptually divided into three major types: stromal, secretory and necrotic. The stromal type develops
through hyalinization of the stroma and appears on MG
images as coarse calcifications. Secretory calcifications
develop through crystallization of secretions and areseen in benign mastopathy as well as low grade breast
carcinoma. On MG images, they appear as small roundor amorphous calcifications. Necrotic calcifications arecaused by comedonecrosis. Studies have shown that in
the tumor of breast carcinoma, necrosis occurs as a result of poor blood flow caused by rapid growth and calcium deposits form in those areas.20–22 On MG images,
necrotic type appear as pleomorphic or linear/branchingcalcifications. The stromal type of calcifications is diagnosed as benign, the necrotic type as malignant, and thesecretory type are seen in a variety lesions of both benign and malignant conditions. Among the calcifications
detected by MG images, detected rate of calcifications
with US images was higher in necrotic type than secretory type. And US examination showed 92.6% sensitivity for detecting necrotic calcifications. Secretary typecalcifications are smaller and paler than necrotic type,therefore, it could be closed in the surrounding mammary gland composition, and it seemed to be false negative on US images. These findings indicate that necrotic
calcifications could be detected easier with US images
in invasive carcinoma.

(%)

**

60
40
20
0

Microcalcification

Microcalcification

Fig. 3. The average value of MIB-1 index was 34.8% for the patients with microcalcifications (n = 27), whereas 22.0% for those
without microcalcifications (n = 52). **P < 0.01.

DISCUSSION
In this study, there were some cases without confirmation of microcalcifications on pathological specimens,
though microcalcifications were found clearly on MG
images. Sensitivity and specificity to detect microcalcifications on MG images were good with 89.7% and 90.7%
respectively.6 Therefore, we defined microcalcifications
detected by MG images as positive cases of microcalcifications.
Most studies conducted on the performance of
US for detecting microcalcifications have focused on
DCIS.1–3, 5 Nagashima et al.1 found that the detection
rate of microcalcifications with US images was higher
for comedo type of DCIS than non comedo type. However, there have been few studies on the significance of
microcalcifications in invasive carcinoma. In this study,
we compared the presence of microcalcifications on US
images to findings of MG images and clinical pathology,
to interpret the significance of detection of microcalcifications on US images.
In our study, patients without microcalcifications
on US images were significantly more likely to have theLuminal A subtype and a lower nuclear grading. Many
previous studies have shown that the patients with Luminal A subtype have a good outcome compared with theother subtypes due to high hormone sensitivity and low
expression of proliferative genes.7–10 The nuclear grading of invasive ductal carcinoma has also been shown to
be useful as an indicator of degree of malignancy and asa clinical prognostic factor, with higher nuclear grading
having a less favorable prognosis.11, 12 Seo et al.13 foundthat overexpression of human epidermal growth factor
92Microcalcification in breast carcinoma

In conclusion, this study suggest that the detection
ability of microcalcifications on US was inferior to MG,
but microcalcifications of tumors detected by US images
could easily serve as an useful prediction to evaluate thedegree of malignancy, furthermore, it may be possible todecide the selection of adjuvant chemotherapy. In addition, US examination can check it repeatedly without aradiation exposure, and may be useful method to detect
the tumor for the patients with dense breast.23 We considered that preoperative US is useful diagnostic tool forthe patients with breast disease.

10 Wirapati P, Sotiriou C, Kunkel S, Farmer P, Pradervand S,
Haibe-Kains B, et al. Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast
cancer subtyping and prognosis signatures. Breast Cancer
Res. 2008;10:R65. PMID: 18662380.
11 Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S,
Watanabe S, et al. Correlation between histologic grade ofmalignancy and copy number of c-erbB-2 gene in breast
carcinoma. A retrospective analysis of 176 cases. Cancer.
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12 The Japanese Breast Cancer Society, editor. General Rules forClinical and Pathological Recording of Breast Cancer. 17thed. Tokyo: Kanehara-shuppan; 2012. p. 64-67. Japanese.
13 Seo BK, Pisano ED, Kuzimak CM, Koomen M, Pavic D, Lee
Y, et al. Correlation of HER-2/neu overexpression with mammography and age distribution in primary breast carcinomas.
Acad Radiol. 2006;13:1211-8. PMID: 16979070.
14 Kato T, Kameoka S, Kimura T, Nishikawa T, Kobayashi M.
Blood vessel invasion as a predictor of long-term survival for
Japanese patients with breast cancer. Breast Cancer Res Treat.
2002;73:1-12. PMID: 12083626.
15 Yagata H, Harigaya K, Suzuki M, Nagashima T, Hashimoto
H, Ishii G, et al. Comedonecrosis is an unfavorable marker
in node-negative invasive breast carcinoma. Pathol Int.
2003;53:501-6. PMID: 12895228.
16 de Azambuja E, Cardoso F, de Castro G, Colozza M, ManoMS, Durbecq V, et al. Ki-67 as prognostic marker in earlybreast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007;96:1504-13. PMID:
17453008.
17 Silverstein MJ, Skinner KA, Lomis TJ. Predicting axillary
nodal positivity in 2282 patients with breast carcinoma. WorldJ Surg. 2001;25:767-72. PMID: 11376414.
18 Cummings MC, Walsh MD, Hohn BG, Bennett IC, Wright
RG, McGuckin MA. Occult axillary lymph node metastases
in breast cancer do matter: results of 10-year survival analysis.
Am J Surg Pathol. 2002;26:1286-95. PMID: 12360043.
19 Hansen NM, Grube B, Ye X, Turner RR, Brenner RJ,
Sim MS, et al. Impact of micrometastases in the sentinelnode of patients with invasive breast cancer. J Clin Oncol.
2009;27:4679-84. PMID: 19720928.
20 Japan Radiological Society, Japanese Society of Radiological Technology, editors. [Mammography guidelines]. Tokyo:
Igaku-shoin; 2011. p. 69-74. Japanese.
21 Tse GM, Tan PH, Cheung HS, Chu WC, Lam WW. Intermediate to highly suspicious calcification in breast lesions:a radio-pathologic correlation. Breast Cancer Res Treat.
2008;110:1-7. PMID: 17674189.
22 Kurebayashi J, Kurosumi M, Sonoo H. A new human breast
cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice. Br J Cancer. 1996;74:200-7. PMID:
8688322.
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The authors declare no conflict of interest.

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