Original Article

Yonago Acta medica 2016;59:163–168

Correlation between Ultrasound Findings of Tumor Margin and Clinicopathological Findings in Patients with Invasive Ductal Carcinoma of the Breast
Naoko Sannomiya,* Yuiko Hattori,* Naoyuki Ueda,* Akira Kamida,* Yuki Koyanagi,* Haruki Nagira,* Saeko
Ikunishi,* Kenta Shimabayashi,* Yuki Hashimoto,* Aya Murata,* Kengo Sato,* Yumi Hirooka,† Keiko Hosoya,†Kiyosuke Ishiguro,‡ Yoko Murata† and Yasuaki Hirooka**Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Yonago 6838503, Japan, †Division of Breast and Endocrine Surgery, Tottori University Hospital, Yonago 683-8504, Japan and ‡Division of Breastand Endocrine Surgery, Ichinomiyanishi Hospital, Ichinomiya 494-0001, Japan

ABSTRACTbe malignant and proliferative than those with indistinct
margins.

Background

Breast ultrasound findings regarding tumor margins are crucial in judging whether a tumor ismalignant or benign. However, the relationships between
the margins and clinicopathological characteristics remain largely unknown. In this study, we examined theclinicopathological characteristics of patients with invasive ductal carcinoma whose ultrasound images showedeither well-defined and rough or indistinct margins.
Methods Of all consecutive patients diagnosed withinvasive ductal carcinoma at the Division of Breast andEndocrine Surgery of Tottori University Hospital fromJanuary 2012 to December 2014, 122 patients whose
ultrasound images showed either “well-defined andrough” or “indistinct” tumor margins were included inthis study. Mammography and ultrasound images taken
at the initial examination were reviewed. Patients weredivided into two groups based on ultrasound findings ofthe tumor margins: the “well-defined and rough group”
and the “indistinct group.” The relationships among
ultrasound findings, mammography findings and clinicopathological findings were investigated in the twogroups.
Results The well-defined and rough group was more
likely to contain solid-tubular carcinoma, while theindistinct group was more likely to contain scirrhous
carcinoma. The MIB-1 index was higher in the well-defined and rough group than in the indistinct group. Additionally, the proportion of patients with nuclear grade
3, estrogen receptor-negative/progesterone receptor-negative, and triple-negative breast cancer was greater inthe well-defined and rough group than in the indistinctgroup.
Conclusion Invasive ductal carcinomas with well-defined and rough margins on ultrasound were likely to

Key words breast cancer; margin; ultrasound imaging

Breast ultrasound findings, such as the shape, margins,posterior features, and depth/width ratio of a tumor,
play an important role in judging whether the tumor ismalignant or benign.1, 2 Hong et al.1 reported that 90%
of tumors with circumscribed margins on ultrasoundwere benign, while 86% of those with spiculated margins were malignant. Rahbar et al.2 reported that 91% of
tumors with circumscribed margins were benign, 67%of those with spiculated or microlobulated margins were
malignant, and 50% of those with ill-defined margins
were malignant.
The Guidelines for Breast Ultrasound Diagnosis by
the Japan Association of Breast and Thyroid Sonology3
state that the margins of tumor lesions can be grouped
into circumscribed, well-defined and rough, or indistinct. These guidelines also state that tumors with circumscribed margins are more likely to be benign, whiletumors with the other two types of margins are likely to
be malignant.3 In breast cancer, the relationship between
clinicopathological characteristics and the type of tumor
margins judged on ultrasound has rarely been investigated.
We examined the clinicopathological characteristics
of invasive ductal carcinoma showing either well-definedand rough or indistinct margins on ultrasound.
SUBJECTS AND METHODSPatients

Of all consecutive 204 patients diagnosed with invasive
ductal carcinoma at the Division of Breast and Endocrine Surgery of Tottori University Hospital from January 2012 to December 2014, six patients with a historyof breast cancer, 21 invasive carcinoma of special types,
32 noninvasive carcinoma, 17 patients with treatmentof neoadjuvant chemotherapy, three bilateral carcinoma
were excluded. Of the other 125 patients, three patients

Corresponding author: Yasuaki Hirooka, MD, PhD
yhirooka@med.tottori-u.ac.jp
Received 2016 March 2
Accepted 2016 May 8
Abbreviations: ER, estrogen receptor; HER2, human epidermal
growth factor receptor type 2; PgR, progesterone receptor; TNBC,
triple negative breast cancer

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N. Sannomiya et al.

posterior features (accentuation, unchanging, or shadowing), echogenic foci (present or absent), interruptionof the interface between adipose tissue and mammary
gland (present or absent), and depth/width ratio (< 0.7 or≥ 0.7).
Mammographic findings were analyzed based on
the Mammography Guideline (3rd expanded edition),4
and the following parameters were assessed: microcalcification (present or absent), architectural distortion (present or absent), and breast density (< 50% or ≥ 50%).
Ultrasound images were reviewed individually bya medical breast cancer specialist with > 25 years ofexperience and an ultrasonographer with > 2 years ofexperience. Mammography images were reviewed by
two medical breast cancer specialists with > 25 years ofexperience in breast examination. All examiners wereblinded to the patients’ information during the evaluation. If there was disagreement in the evaluation of findings, a final decision was reached by consensus.

whose ultrasound images showed circumscribed of
the tumor margins were excluded because they are too
small population to analyze the relationship between theultrasound images of the tumor margins and their clinicopathological characteristics. Thus, 122 patients whose
ultrasound images showed either “well-defined andrough” or “indistinct” tumor margins were included inthis study. Mammography and ultrasound images taken
at the initial examination were reviewed.
The largest masses were evaluated in patients withmulticentric breast cancer.
Clinical findings

Age, levels of tumor markers (carcinoembryonic antigen
and cancer antigen 15-3) and menopause status were investigated.
Imaging analysis

The findings of mammography and ultrasound examinations performed at the initial examination were reviewed. Patients were divided into the well-defined andrough group and the indistinct group based on the ultrasound findings of the tumor margins. Well-defined andrough margins were defined as relatively clear but roughinterfaces between tumor and non-tumor regions, while
indistinct margins were defined as unclear interfaces
between the above two regions (Figs. 1A and B). There
were 38 tumors with two types of tumor margins. Suchcases were classified as a margin of more widely recognition.
Ultrasound examinations were performed with either a HI VISION Preirus diagnostic ultrasound system(Hitachi Aloka Medical, Tokyo, Japan) with a EUPL74M linear probe (5.0–13.0 MHz) or a Noblus system(Hitachi Aloka Medical) with a EUP-L75 linear probe(5.0–18.0 MHz).
Ultrasound findings were analyzed based on the
Guidelines for Breast Ultrasound Diagnosis (3rd edition),3 and the following parameters were assessed: tumor size, homogeneity (homogeneous or heterogeneous),A

Histological analysis

In all cases, we examined the histological classification,
expression of hormone receptors [estrogen receptor (ER)and progesterone receptor (PgR)], expression of humanepidermal growth factor receptor type 2 (HER2), lymphatic vessel invasion, blood vessel invasion, nuclear
grade, lymph node metastasis, and MIB-1 index. The
histological classifications were classified into papillotubular carcinoma, solid-tubular carcinoma, and scirrhous
carcinoma in accordance with the General Rules forClinical and Pathological Recording of Breast Cancer(17th edition),5 and nuclear types were also classified
into grades 1 to 3. Intrinsic subtypes were classified
in accordance with the St. Gallen International Expert
Consensus on the Primary Therapy of Early Breast
Cancer 2013.6 Luminal A, luminal B, and HER2-positive breast cancer was termed non-triple-negative breast
cancer (non-TNBC) and compared with triple-negative
breast cancer (TNBC).

Fig. 1. Ultrasound findings of tumor margin.
A: An ultrasound image showeda well-defined and rough margin
with posterior accentuation.
B: An ultrasound image showed
an indistinct margin with posterior
shadowing.

B
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Tumor margin in breast cancer

DISCUSSION
This study showed that breast cancers with well-definedand rough margins on ultrasound had a high nuclear
grade and MIB-1 index, suggesting that they have ahigher degree of malignancy and greater proliferative
capacity. Additionally, well-defined and rough margins
on ultrasound were more likely to be solid-tubular carci-

Statistical analysis

The relationships among ultrasound findings, mammography findings and clinicopathological findings were
investigated with respect to tumor margins in the twogroups. Statistical analyses were performed with theuse of statistical software, SPSS, version 23.0 (IBM,Armonk, NY), and P < 0.05 indicated a statisticallysignificant difference. Quantitative data were analyzed
using Fisher’s exact test and Pearson’s chi-square test,
while continuous data were analyzed using the Mann–
Whitney U test.
This study was approved by the Ethics Committeeof the Tottori University Medical School (approval number 2103).

Table 2. Relationships between tumor margin typeand ultrasound findings
MarginWell definedand roughTumor size, mm

Indistinct

17.1 (13.8–23.5) 15.2 (11.0–22.8) 0.911

Homogeneity

RESULTS
All patients were women with a mean age of 61 years(range, 28–88 years). There were no significant differences in age, tumor marker levels or menopause status
between the two groups (Table 1).
The 122 patients were grouped into the well-definedand rough group (n = 49) and the indistinct group (n =73). Accentuation of posterior features was observed
more frequently in the well-defined and rough group,
while shadowing was observed more frequently in theindistinct group (P < 0.001) (Table 2). There were no relationships between ultrasound findings regarding margins and mammography findings (Table 3).
The pathological examination results are shownin Table 4. Tumors in the well-defined and roughgroup were more likely to be solid-tubular carcinomas,
ER-negative, PgR-negative, nuclear grade 3, and TNBC(P = 0.003) and to have a higher MIB-1 index. Conversely, tumors in the indistinct group were more likely to bescirrhous carcinomas (P < 0.001), ER-positive (P < 0.05),
PgR-positive (P < 0.01), and nuclear grade 1 (P = 0.001)
and to have a lower MIB-1 index (P = 0.001).

0.072

Homogeneous

6

19

Heterogeneous

43

54

Accentuation

28

13

Unchanging

15

32

Shadowing

6

28

21

28

Absent28
Interrupting of theinterface between
adipose tissue andgland
Present
39

45

Posterior features< 0.001

Echogenic fociPresent

AbsentP-value

0.707

0.635
61

10

12

< 0.7

23

28

≥ 0.7

26

45

Depth/width ratio

0.357

Variables of tumor size are reported as median (interquartile
range).
Table 3. Relationships between tumor margin typeand mammography findings

Table 1. Relationships between tumor margin typeand clinical findings

MarginWell definedand roughIndistinct

Present

17

27

Absent32

46

MarginWell definedand roughIndistinct

Age, years old

60 (48–70)

62 (53–70)

0.441

CEA, ng/mL

1.9 (1.1–3.0)

1.6 (1.2–2.7)

0.450

CA15-3, U/mL

11.9 (8.3–16.0)

11.1 (9.3–17.8)

0.766

Menopausal status

Microcalcifications

P-value

Premenopausal 14

13

Postmenopausal 35

60

0.849

Architectural distortion

0.186

0.099

Present3

13

Absent

46

60

< 50%

28

51

≥ 50%

21

22

Breast density

All variables are reported as median (interquartile range).
CA15-3, cancer antigen 15-3; CEA, carcinoembryonic antigen.

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P-value

0.178

N. Sannomiya et al.

nomas than indistinct margins. Additionally, almost allcases of TNBC were observed among the tumors withwell-defined and rough margins.
Highly proliferative breast cancers reportedly do
not induce a stromal reaction and thus show pushingborders, while poorly proliferative tumors induce a desmoplastic reaction resulting in the formation of dense
fibrous tissue.7–9 Additionally, Boisserie-Lacroix et al.10

reported that breast cancers of low malignancy (histological grades 1 and 2) showed spiculated margins andechogenic halos around lesions attributed to a stromal
reaction, while highly malignant breast cancers (histological grade 3) did not cause a stromal reaction andappeared as a round mass. It is likely that invasive ductal carcinomas with well-defined and rough margins,as seen in this study, were highly proliferative withoutcausing a stromal reaction, and therefore grew by pushing the surrounding tissues. This theory is in agreementwith another set of findings indicating that such invasive
ductal carcinomas were often solid-tubular carcinomas
with relatively clear margins and that accentuation of
the posterior features was caused by enrichment of thecellular component. Conversely, invasive ductal carcinomas with indistinct margins were thought to be of
low malignancy and caused Indian filing invasion andstromal reaction, resulting in indistinctive margins on
the sonogram. Furthermore, fine stands of cancer cells
infiltrating into the surrounding tissue appeared to cause
backscattering, resulting in posterior shadowing.
Several studies have examined the relationships
between ultrasound images and pathological findings.
Çelebi et al.11 showed that hormone receptor-positive
breast cancers showed noncircumscribed margins withposterior shadowing, while TNBCs showed circumscribed margins. Additionally, Aho et al.12 demonstrated
that breast cancers showing shadowing or unchanging
posterior features were histologically low-grade andER-positive, while those showing enhanced posteriorfeatures were ER-negative. Furthermore, breast cancers
with circumscribed margins, especially those in elderly
patients, were highly malignant and hormone receptor-negative. These previous findings are in good agreement with our findings that invasive ductal carcinoma
without indistinct margins were of nuclear grade 3 andhormone receptor-negative.
Lamb PM et al.13 reported that breast cancers withshadowing posterior features on ultrasound were of histological grade 1, but they reported no significant differences in ultrasound findings regarding margins. Çeleci
et al.11 speculated that this was because the Breast Imaging Reporting and Data System Lexicon for Ultrasoundwas not used to classify the ultrasound findings. Furthermore, in contrast to our findings, Rotstein and Neerhut14
showed that grade 3 invasive ductal carcinoma showed
spiculated, microlobulated, and angular margins. However, Rotstein and Neerhut examined histological grade
3 cases only, and did not compare them with grade 1
and 2 cases; this may explain the difference from ourfindings.
TNBC is reportedly highly malignant, and theTable 4. Relationships between tumor margin type
and pathological findings
MarginMIB-1 index, %Well definedand roughIndistinct

P-value

31.0(22.0–44.0)

20.1(13.0–32.0)

0.001

Histological classification
Papillotubular 16
carcinoma
Solid-tubular21
carcinoma
Scirrhous carci12
noma
ER< 0.001
24
8
41
0.046

Positive

39

68

Negative

10

5

Positive

32

63

Negative

17

10

Positive

10

12

Negative

39

61

PgR

0.008

HER-2

0.635

Nuclear grade

0.001

Grade 1

11

34

Grade 21224

Grade 3

26

15

TNBC

0.003

TNBC

8

1

non-TNBC

41

72

Lymphatic vessel invasion

0.848

Present

19

26

Absent30

47

Blood vessel invasion

1.000

Present22

Absent47

71

Lymph node metastasis

0.217

Present17

17

Absent32

56

Variables of MIB-1 index are reported as median (interquartile
range). ER, estrogen receptor; HER2, human epidermal growth
factor receptor type 2; PgR, progesterone receptor; TNBC, triple-negative breast cancer.

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Tumor margin in breast cancer
The authors declare no conflict of interest.

histological grade, nuclear grade, and Ki-67 level arehigher and the prognosis is poorer than those of othersubtypes.15–18 In terms of the relationship between ultrasound findings and breast cancer subtypes, TNBC isoften associated with circumscribed margins, no shadowing of posterior features, marked hypoechogenicity,no calcification, and a large depth/width ratio.19, 20 However, about 18% of TNBC tumors had circumscribedmargin,21 and TNBCs itself were about only 15% of allbreast cancer.22 Thus, TNBC tumors with circumscribedmargins are small part in all breast cancer, and it wasthought that many of tumors with circumscribed margin
would be benign lesions. Actually, tumors with circumscribed margin were only three cases in this study.
Furthermore, our study also showed that there weremore TNBCs among invasive ductal carcinomas withwell-defined and rough margins than among those withindistinct margins.
In this study, the patients with large tumors were excluded because they received neoadjuvant chemotherapy.
This result may explain that there was no relationshipbetween tumor margin types and tumor size.
Poor prognostic factors of invasive ductal carcinoma
include young age, vessel invasion, high tumor diameter,high nuclear grade, high histological grade, high degreeof proliferation, absence of hormone receptor expression,
overexpression of HER2, and lymph node metastasis.6,
23, 24
In addition, the expression levels of the hormone
receptors Ki-67 and HER2 are particularly important indetermining the optimal therapeutic strategy.6 The present study showed that invasive ductal carcinomas withwell-defined and rough margins on ultrasound comprised a large proportion of hormone receptor-negativecancers, high nuclear grades, TNBCs and high MIB1 indices, suggesting a poor prognosis in these cases.
This knowledge can predict important prognostic andtherapeutic factors such as the proliferative potential andexpression levels of hormones by ultrasound, making it
possible to predict the prognosis and determine the optimal therapeutic strategy earlier.
Our study has several limitations. First, our results
are not applicable to noninvasive carcinoma or invasive
carcinoma of special types because these carcinomas
were excluded in this study. Second, the amount of stromal tissue changes and invasion types were not assessedby histopathology. This needs to be done to investigate
the relationship between histopathologic findings andultrasound findings.
In conclusion, invasive ductal carcinomas withwell-defined and rough margins on ultrasound are more
likely to be malignant and proliferative than those withindistinct margins.

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