Mammographic and Sonographic Features of Triple-Negative Invasive Carcinoma of No Special Type

Ultrasound in Med. & Biol., Vol. 41, No. 2, pp. 375–383, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter

http://dx.doi.org/10.1016/j.ultrasmedbio.2014.09.006

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Original Contribution MAMMOGRAPHIC AND SONOGRAPHIC FEATURES OF TRIPLE-NEGATIVE INVASIVE CARCINOMA OF NO SPECIAL TYPE HYUN KYUNG JUNG,*y KYUNGHWA HAN,z YEO JIN LEE,* HEE JUNG MOON,* EUN-KYUNG KIM,* and MIN JUNG KIM* * Department of Diagnostic Radiology, Severance Hospital, Research Institute of Radiologic Science, Yonsei University College of Medicine, Seoul, Korea; y Department of Diagnostic Radiology, College of Medicine, Haeundae Paik Hospital, Inje University, Busan, Korea; and z Department of Diagnostic Radiology, Research Institute of Radiologic Science, Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea (Received 21 April 2014; revised 29 August 2014; in final form 2 September 2014)

Abstract—The aim of this study was to compare the mammography, ultrasound (US) and histologic features of triple-negative (TN) invasive carcinoma of no special type (NST) to non-TN invasive carcinoma of NST. The second aim was to assess whether the distinct imaging characteristics of TN breast cancer would persist after controlling for the histologic features. A total of 344 invasive carcinomas of NST in 337 patients from January 2007 to February 2008 were included in this study. Two radiologists retrospectively reviewed the mammography and US findings using the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon and our institution’s criteria. On mammography, TN invasive carcinoma of NST most commonly presented as a mass with round shape and non-spiculated margin. On US, it was more likely to have internal hypoechogenicity, an abrupt boundary and posterior acoustic enhancement. TNBC lacked major suspicious imaging findings such as an irregular shape, spiculated margin and calcification. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Triple-negative breast cancer, Invasive carcinoma of no special type, Mammography, Ultrasound.

Triple-negative breast cancer (TNBC) is characterized by negative expressions of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). According to gene expression profiles, there are five subtypes of breast cancer: luminal A, luminal B, normal breast-like, HER2 enriched, and basal-like. Although not completely overlapping with the characteristics of basal-like breast cancer, recent studies suggest that the characteristics of TNBC roughly equate to those of the basal-like subgroup of breast cancers (Ko et al. 2010; Rakha et al. 2007, 2008; ReisFilho and Tutt 2008). TNBC is more likely to affect younger patients and is more prevalent in AfricanAmerican and Hispanic women (Whitman et al. 2011). It is known to be associated with aggressive clinical behavior and poor clinical outcomes. Moreover, there is currently no effective targeted therapy available because

endocrine therapy and anti-HER2 therapy are ineffective in patients with TNBC. There have been multiple reports on mammography and ultrasound (US) features of TNBC (BoisserieLacroix et al. 2012; Choi et al. 2011; Dogan et al. 2010; Ko et al. 2010; Kojima and Tsunoda 2011; KrizmanichConniff et al. 2012; Wang et al. 2008; Wojcinski et al. 2012; Yang et al. 2008). Most studies have found that TNBC lacks some characteristics of malignancy and tends to present as a circumscribed mass that has unassociated microcalcifications, which are correlated with a high histologic grade (Ko et al. 2010). Because TNBC is made up of a heterogeneous group of breast cancers, it includes adenoid cystic, juvenile secretory, apocrine, medullary and metaplastic carcinomas as well as invasive carcinoma of no special type (NST) (Lakhani et al. 2012; Bonzanini et al. 2012). In contrast to invasive carcinoma of NST, the remaining carcinomas often present with more benign-looking imaging features (Billar et al. 2010; Meyer et al. 1989; Yang et al. 2007). Although there have been no previous studies focusing primarily on imaging findings of TN invasive carcinoma of NST,

Address correspondence to: Min Jung Kim, MD, Department of Radiology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. E-mail: [email protected] 375

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we hypothesized that mammography and US features of TN invasive carcinoma of NST may be similar to those mentioned in previous reports and that our study would also add to earlier research that found that imaging features of TNBC are results of high histologic grades. We evaluated and compared the mammography, US and histologic features of TN invasive carcinoma of NST with those of non-TN invasive carcinoma of NST. In addition, we assessed whether the distinct imaging characteristics of TNBC persisted after controlling for the histologic features. MATERIALS AND METHODS Patient selection The Institutional Review Board approved this retrospective study and waived informed consent. Using a computerized search of the radiologic database at our hospital, we identified 720 patients who had undergone pre-operative imaging evaluations before surgery between January 2007 and February 2008. We retrospectively reviewed the clinicoradiologic manifestations and the surgically confirmed pathologic testing results using the patients’ medical records. At the time of study design in 2012, we initiated a different study evaluating the magnetic resonance (MR) findings of TNBC using data gathered between 2009 and 2011 at our institution, which was recently accepted for publication (Acta Radiologica). Therefore, we used theses previous cases to avoid duplication of data. Furthermore, we used the same American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) lexicon for the imaging findings, and we determined there were no substantial differences based on the time span. Among them, 383 patients were excluded according to the exclusion criteria, which were as follows: in situ carcinoma without an invasive component (n 5 116); non-ductal carcinoma of no special type (n 5 92); no surgical pathologic testing results available because surgery was performed at an outside hospital (n 5 19); no information available on HER2 or hormone receptor status (n 5 35); no pre-operative imaging findings available because of unavailable mammography results (n 5 47) or status post-excision (n 5 13) and a history of breast cancer surgery (n 5 23), which can influence radiologic analysis and neoadjuvant chemotherapy before surgery (n 5 38). The remaining 337 patients with 344 invasive carcinomas of NST were included in this study. Imaging evaluation and analysis Mammography was performed by one of two mammography technologists, using a dedicated full-field digital mammography system (Lorad/Hologic, Danbury, CT, USA). Standard mediolateral oblique and craniocau-

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dal views were routinely obtained, and additional views were obtained when necessary. Magnification and spot compression mammograms (n 5 127) were performed to further evaluate the tissue for microcalcification or asymmetry or to better characterize the mass margin. One of six dedicated breast imaging radiologists with 1–11 y of experience performed a bilateral whole-breast US using a 7–15 MHz linear array transducer (HDI 5000; Philips Healthcare, Bothell, WA, USA; Logic 9; GE Medical Systems, Milwaukee, WI, USA) with the patient in the supine position and the patient’s arm raised above the head. All radiologists who performed the breast US were fully aware of the BI-RADS lexicon (American College of Radiology 2003) and routinely obtained gray-scale images (transverse and sagittal planes). If necessary, additional images such as a radial or anti-radial image, color Doppler images and the maximal lesion diameter were obtained. The mammography and US findings were evaluated according to the ACR BI-RADS lexicon and our hospital data (Kim et al. 2008). The BI-RADS descriptors were as follows: On mammography, breast density was classified as fatty, scattered fibroglandular, heterogeneously dense or extremely dense. Each lesion was described as a mass (shape, margin and density), calcification (morphology and distribution), architectural distortion or asymmetry. On US, each mass was described as follows: shape (oval, round or irregular), margin (circumscribed, microlobulated, indistinct, angular or spiculated), orientation (parallel or not parallel), lesion boundary (abrupt or echogenic halo), echo pattern (anechoic, hyperechoic, isoechoic, hypoechoic or complex echoic) and posterior acoustic features (none, enhancement or shadowing). We divided suspicious mammography and US findings into major (irregular shape, spiculated margin and microcalcification) and minor criteria (round shape, not circumscribed margin, not parallel orientation, duct extension, complex echogenicity and posterior shadowing) to further characterize the mass. Any suspicious mammography and US finding was defined as at least one of the suspicious findings according to the major and minor criteria, as mentioned earlier. All available mammography and US images of the 344 breast cancer patients were retrospectively reviewed by two radiologists with 1 and 8 y of experience in breast imaging, respectively, without knowledge of the breast cancer subtypes. Two radiologists independently evaluated all cases, and then consensus was reached. In cases of disagreement, the most suspicious features or appropriate term able to be represented on the mammography or US was determined. Inter-observer variability was inevitable, as in previous reports, where two radiologists retrospectively reviewed in consensus (Lee et al. 2008). A retrospective review of mammography and US images

Features of triple-negative breast cancer d H. K. JUNG et al.

was performed using digitized static images on a 5 MP monochrome display monitor (ME551 i2, Totoku, Electric Co., Tokyo, Japan) of a picture archiving and communication system. Histopathologic analysis We retrospectively reviewed the previous pathologic results and did not perform a new pathology slide review. Histopathologic analysis was performed to determine tumor grade, nuclear grade, hormone receptor (HR) status and HER2 status through surgical specimens. ER, PR and HER2 status were determined using immunohistochemistry. For ER and PR, tumors with $10% nuclearstained cells were considered positive. HER2 status was graded as 0, 11, 21, and 31 using the Hercep Test (Dako, Glostrup, Denmark) following the manufacturer’s guidelines (Wolff et al. 2007). Status results were considered positive when strong membranous staining (31) was observed, whereas results with 0–11 staining were regarded as negative. Beginning in 2005 at our facility, when a tumor was scored as 21, the pathologist recommended an additional fluorescence in situ hybridization (FISH). After notifying the primary physician and obtaining patient’s consent, a second examination was performed using the PathVysion HER-2-DNA Probe Kit (Abbott Laboratories, Abbott Park, IL, USA). Eleven cases with 21 staining underwent FISH and three cases were confirmed to have HER2 overexpression. Thirtyfour cases with 21 staining were excluded because they did not undergo FISH. The histologic grade of invasive carcinoma was divided into grade 1 (well differentiated), grade 2 (moderately differentiated) or grade 3 (poorly differentiated) according to the Scarff-BloomRichardson System (Bloom and Richardson 1957). The nuclear grade of invasive carcinoma was divided into grade 1 (small, regular uniform cell), grade 2 (moderate nuclear size and variation) or grade 3 (marked nuclear variation). A total of 344 invasive carcinomas of NST were categorized into four groups according to tumor phenotypes ER, PR and HER2 as follows; HR–/HER2– (TNBC), HR1/HER2– (luminal A), HR–/HER21 (HER2-enriched), and HR1/HER21 (luminal B). The latter three were the non-TNBC groups. Statistical analysis Clinicoradiologic findings were compared among the four groups according to ER, PR and HER2. Statistical comparisons were performed using a t-test for parametric variables and a chi-square test or Fisher’s exact test for nonparametric variables. Statistical significance was assumed when the two-sided p value was less than 0.05. Univariate and multiple logistic regression analysis were performed to assess the odds ratio with 95% confidence intervals (CI). This was done to evaluate the rela-

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tive impact of the four groups and tumor grade on respective imaging findings. The histologic or nuclear grade may be a strong confounder for determining TNBC imaging finding; therefore, a multiple logistic regression analysis was performed after controlling for the tumor grades. Data were analyzed by a statistician using SAS software (SAS System Version 9 for Microsoft Windows, SAS Institute Inc., Cary, NC, USA). RESULTS When classifying the tumor subtypes of the 344 invasive carcinomas of NST in 337 patients, 70 (20.3%) were TNBC, 189 (54.9%) were luminal A, 39 (11.3%) were HER2-enriched and 46 (13.4%) were luminal B. All patients were women and the age at diagnosis ranged from 29 to 78 y (mean age, 50.3 y). The mean age of patients was 49.8 6 10.36 y for patients with TNBC, 50.1 6 9.75 y for luminal A, 52.9 6 7.33 y for HER2enriched and 48.5 6 10.24 y for luminal B, respectively (p 5 0.217). The mean tumor size of patients also differed with no statistical significance and were as follow: TNBC (20.67 6 14.52 mm), luminal A (18.28 6 8.73 mm), HER2-enriched (22.82 6 9.66 mm) and luminal B (19.51 6 8.34 mm), respectively (p 5 0.062). The overall characteristics of the 344 invasive carcinomas of NST according to tumor phenotype have been summarized in Table 1 (Figs. 1-4). For tumor grade, TNBC had a high histologic and nuclear tumor grade compared with non-TNBC (p , 0.0001). On mammography, TNBC most commonly presented as a round mass with non-spiculated margins (p , 0.05). On US, it was more likely to have internal hypoechogenicity, an abrupt boundary and posterior acoustic enhancement (p , 0.05). TNBC also tended to have a high density on mammography (p 5 0.053) and a non-parallel orientation on US (p 5 0.009) with marginal statistical significance. Considering the respective non-TNBC groups— luminal A, HER2-enriched and luminal B—there were statistically significant differences in mammographic presentations such as mass shape and mass margin and US findings such as internal echogenicity and presence of calcifications among the four groups. Breast density according to the BI-RADS lexicon was not significantly different in TNBC compared with non-TNBC. Regarding histologic and nuclear tumor grade, the four groups had different distributions with statistical significance. The HER2-enriched group and the TNBC group were more likely to have a high histologic and nuclear tumor grade. Table 2 shows the results of logistic regression analysis that compared representative radiologic findings of TNBC and each non-TNBC subtype. We found differences in radiologic presentation such as mass margin on mammography and lesion boundary as well as

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Table 1. Characteristics of 344 invasive carcinomas of no specific type according to tumor phenotypes

Age (y) Mean ,30 30–40 40–50 50–60 .60 Histologic tumor grade Low grade Intermediate grade High grade Nuclear tumor grade Low grade Intermediate grade High grade Mammographic findings Mammographic presentation Negative Mass Calcifications Mass with calcifications Asymmetry or distortion Mammographic parenchymal pattern ,50% .50% Mass shape Round Oval Lobulated Irregular Mass margin Circumscribed Microlobulated Obscured Indistinct Spiculated Mass density High Iso Low US findings Visible Not visible Mass shape Oval Round Irregular Mean tumor size (mm) Orientation Parallel Non-parallel Margin Circumscribed Indistinct Microlobulated Angular Spiculated Boundary Abrupt Echogenic halo Internal echogenicity Hyperechoic Isoechoic Hypoechoic Calcifications None Microcalcifications

TNBC n 5 70

Non-TNBC n 5 274

49.8 1 (1.4) 10 (14.3) 28 (40.0) 20 (28.6) 11 (15.7)

50.2 2 (0.7) 38 (13.9) 115 (42.0) 77 (28.1) 42 (15.3)

9 (12.9) 26 (37.1) 35 (50.0)

87 (31.8) 140 (51.1) 47 (17.1)

3 (4.3) 23 (32.9) 44 (62.9)

41 (15.0) 147 (53.6) 86 (31.4)

6 (8.6) 36 (51.4) 5 (7.1) 14 (20.0) 9 (12.9)

31 (11.3) 116 (42.3) 51 (18.6) 46 (16.8) 30 (10.9)

22 (31.4) 48 (68.6)

60 (21.9) 214 (78.1)

31 (62.0) 13 (26.0) 3 (6.0) 3 (6.0)

79 (48.8) 22 (13.6) 12 (7.4) 49 (30.2)

7 (14.0) 15 (30.0) 1 (2) 20 (40.0) 7 (14.0)

13 (8.0) 22 (13.6) 8 (4.9) 35 (21.6) 84 (51.9)

29 (58.0) 21 (42.0) 0 (0.0)

72 (44.4) 85 (52.5) 5 (3.1)

70 (100.0) 0 (0.0)

268 (97.8) 6 (2.2)

17 (24.3) 25 (35.7) 28 (40.0) 20.6

70 (25.5) 60 (21.9) 138 (50.4) 19.0

16 (22.9) 54 (77.1)

83 (30.3) 185 (67.5)

4 (5.7) 11 (15.7) 31 (44.3) 12 (17.1) 12 (17.1)

8 (2.9) 42 (15.3) 79 (28.8) 48 (17.5) 91 (33.2)

50 (71.4) 20 (28.6)

145 (52.9) 123 (44.9)

1 (1.4) 11 (15.7) 58 (82.9)

2 (0.7) 91 (33.2) 175 (63.9)

55 (78.6) 15 (21.4)

179 (65.3) 89 (32.5)

p Value*

Luminal A n 5 189

HER-enriched n 5 39

Luminal B n 5 46

50.1 0 (0.0) 29 (15.3) 84 (44.4) 45 (23.8) 31 (16.4)

52.9 0 (0.0) 2 (6.8) 11 (28.2) 21 (53.8) 5 (12.8)

48.5 2 (4.3) 7 (15.2) 20 (43.5) 11 (23.9) 6 (13.0)

74 (39.2) 88 (46.5) 27 (14.3)

3 (7.7) 20 (51.3) 16 (41.0)

10 (21.7) 32 (69.6) 4 (8.7)

34 (18.0) 113 (59.8) 42 (22.2)

1 (2.6) 12 (30.8) 26 (66.7)

6 (13.0) 22 (47.8) 18 (39.1)

24 (12.7) 93 (49.2) 29 (15.3) 25 (13.2) 18 (9.5)

1 (2.6) 10 (25.6) 15 (38.5) 8 (20.5) 5 (12.8)

6 (13.0) 13 (28.3) 7 (15.2) 13 (28.3) 7 (15.2)

39 (20.6) 150 (79.4)

12 (30.8) 27 (69.2)

9 (19.6) 37 (80.4)

56 (47.5) 15 (12.7) 7 (5.9) 40 (33.9)

13 (72.2) 2 (11.1) 2 (11.1) 1 (5.6)

10 (38.5) 5 (19.2) 3 (11.5) 8 (30.8)

9 (7.6) 14 (11.9) 3 (2.6) 26 (22.0) 66 (55.9)

3 (16.7) 3 (16.7) 2 (11.1) 4 (22.2) 6 (33.3)

1 (3.8) 5 (19.2) 3 (11.6) 5 (19.2) 12 (46.2)

53 (44.9) 63 (53.4) 2 (1.7)

8 (44.4) 8 (44.4) 2 (11.1)

11 (42.3) 14 (53.8) 1 (3.8)

186 (98.4) 3 (1.6)

37 (94.9) 2 (5.1)

45 (97.8) 1 (2.2)

45 (23.8) 42 (22.2) 99 (52.4) 18.2

11 (28.2) 4 (10.3) 22 (56.4) 22.8

14 (30.4) 14 (30.4) 17 (37.0) 19.5

50 (26.5) 136 (72.0)

13 (33.3) 24 (61.5)

20 (43.5) 25 (54.4)

6 (3.2) 30 (15.9) 50 (26.5) 32 (16.9) 68 (36.0)

1 (2.6) 6 (15.4) 13 (33.3) 8 (20.5) 9 (23.1)

1 (2.2) 6 (13.0) 16 (34.8) 8 (17.4) 14 (30.4)

97 (51.3) 89 (47.1)

22 (56.4) 15 (38.5)

26 (56.5) 19 (41.3)

1 (0.5) 71 (37.6) 114 (60.3)

1 (2.6) 8 (20.5) 28 (71.8)

0 (0.0) 12 (26.1) 33 (71.7)

134 (70.9) 52 (27.5)

17 (43.6) 20 (51.3)

28 (60.9) 17 (37.0)

0.734

,0.001

,0.001

0.217

0.454

,0.001

,0.001

0.188 0.006

0.053

,0.001

0.120

0.966

0.973

0.150

0.239 0.099

,0.001

0.019

0.093 ,0.001

p Valuey

0.061

0.780

0.055 0.057 0.170

0.025

0.050

0.049

0.007

0.091

0.002 (Continued )

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Table 1. Characteristics of 344 invasive carcinomas of no specific type according to tumor phenotypes (Continued )

Posterior acoustic change None Enhancement Shadowing

TNBC n 5 70

Non-TNBC n 5 274

49 (70.0) 13 (18.6) 8 (11.4)

200 (73.0) 24 (8.8) 44 (16.0)

p Value*

Luminal A n 5 189

HER-enriched n 5 39

Luminal B n 5 46

145 (76.7) 13 (6.9) 28 (14.8)

26 (66.7) 5 (12.8) 6 (15.4)

29 (63.0) 6 (13.0) 10 (21.7)

p Valuey

0.006

0.120

TNBC 5 triple-negative breast cancer; US 5 ultrasound. The percentages are enclosed in parentheses. * p Value comparing TNBC with non-TNBC lesions. y p Value comparing TNBC, luminal A, HER-enriched, and luminal B lesions.

echogenicity on US. TNBC had a decreased risk for presenting as calcifications on mammography with marginal value (OR: 0.1190; CI: 0.0107–1.3229) compared with HER2-enriched. TNBC also had a decreased risk of showing a spiculated margin on mammography (OR: 0.1343; CI: 0.0382–0.4725; p 5 0.002), echogenic halo on US (OR: 0.4361; CI: 0.2410–0.7891; p 5 0.006) and internal hypoechogenicity on US (OR: 3.1224; CI: 1.5697–6.2110; p 5 0.001) compared with luminal A. Because the histologic and nuclear grades themselves were strong confounders for determining the imaging finding of TNBC, the effect of breast cancer subtypes on radiologic findings was also evaluated by using multiple logistic regressions with adjustment for histologic and nuclear grades (Table 3). Even after adjustment, a high nuclear grade was still an important factor associated with

the presentation of calcifications on mammography (OR: 3.1419; p 5 0.035) and an echogenic halo on US (OR: 1.8956; p 5 0.020). For spiculated margin on mammography, there were differences observed between TNBC and luminal cancers. After adjustment of histologic and nuclear grades, the differences were even more pronounced. Therefore, the spiculated margin on mammography was much more affected by tumor subtype than by histologic and nuclear grade. TNBC was less likely to have spiculated margin (OR: 0.2188; p 5 0.0278) and echogenic halo (OR: 0.3090; p 5 0.0006), while being more likely to have internal hypoechogenicity (OR: 2.3371; p 5 0.0230) compared with luminal A. Although the visualization of microcalcifications on US has a variable relationship with several factors, such as nuclear grade and subtypes of breast cancer, it was mainly affected

Fig. 1. A 41-y-old woman complained of a palpable lump in her left breast. The left (a) mediolateral oblique and (b) craniocaudal mammography indicated a high-density mass directly behind a radiopaque marker with indistinct margin, with round shape and without calcifications (white arrows). (c) Transverse ultrasound revealed a hypoechoic mass with microlobulated margin, round shape, abrupt boundary and minimal posterior acoustic enhancement (white arrows). The mass was assessed as a suspicious abnormality. US-CNB was performed and the mass was confirmed as invasive ductal carcinoma. The patient underwent conservation surgery, which revealed a nuclear grade 3, histologic grade 3 TNBC. TNCB 5 triple-negative breast cancer; US-CNB 5 Ultrasound-guided core needle biopsy.

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Fig. 2. A 37-y-old woman complained of a palpable lump in her left breast. Left (a) mediolateral oblique mammography indicated an isodense mass directly behind a radiopaque marker with spiculated margin, with irregular shape and without calcifications (white arrows). (b, c) Transverse and longitudinal ultrasound revealed a hypoechoic mass with microlobulated margin, oval shape, abrupt boundary and posterior acoustic enhancement (white arrows). US-CNB was performed at outside hospital, and the mass was confirmed as invasive ductal carcinoma. The patient underwent mastectomy and was diagnosed as having nuclear grade 2, histologic grade 2 luminal B breast cancer. US-CNB 5 Ultrasound-guided core needle biopsy.

by tumor subtypes (OR of TNBC: 0.2132; p 5 0.0005) even after adjusting for nuclear grade. DISCUSSION As mentioned previously, we further divided suspicious mammography and US findings into major and minor suspicious findings. We found that the TN invasive carcinoma of NST produced minor suspicious findings. This trend was similar to those in previous studies, which

reported that TNBC tends to present as a circumscribed mass unassociated with microcalcifications (BoisserieLacroix et al. 2012; Choi et al. 2011; Dogan et al. 2010; Ko et al. 2010; Kojima and Tsunoda 2011; Krizmanich-Conniff et al. 2012; Wang et al. 2008; Wojcinski et al. 2012; Yang et al. 2008). Our study found several distinct mammography and US features of TNBC, which are consistent with previous studies. On mammography, TNBC most commonly presented as a mass with round shape and indistinct margin, without

Fig. 3. A 51-y-old woman complained of a palpable lump in her right breast. Right (a) craniocaudal and (b) spot compression mammography indicated a high-density mass directly behind a radiopaque marker with spiculated margin, irregular shape and calcifications (white arrows). (c) Longitudinal ultrasound revealed a hypoechoic mass with angular margin, irregular shape and echogenic halo (white arrows). US-CNB was performed and the mass was confirmed as invasive ductal carcinoma. The patient underwent mastectomy and was diagnosed as having nuclear grade 3, histologic grade 2, HER2-enriched breast cancer. HER2 5 human epidermal growth factor receptor 2; US-CNB 5 Ultrasound-guided core needle biopsy.

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Fig. 4. A 52-y-old woman complained of a palpable lump in her right breast. Right (a) mediolateral oblique mammography indicated a high-density mass directly behind a radiopaque marker with spiculated margin, with round shape and without calcifications (white arrows). (b, c) Transverse and longitudinal ultrasound revealed a hypoechoic mass with non-parallel oriented, spiculated margin; irregular shape; echogenic halo; and posterior acoustic shadowing (white arrows). US-CNB was performed and the mass was confirmed as invasive ductal carcinoma. The patient underwent conservation surgery, which revealed a nuclear grade 3, histologic grade 3, luminal A breast cancer. US-CNB 5 Ultrasound-guided core needle biopsy.

calcifications. There was a trend of high density with marginal significance. Compared with HER2-enriched and luminal A, TNBC had a decreased risk for presenting calcifications and spiculated margin, respectively. Yang

et al. (2008) suggested that the mammographic feature of less associated calcifications can be correlated with a low incidence of ductal carcinoma in situ (DCIS), which reflects a more rapid carcinogenesis without

Table 2. Odds ratio of 70 TN invasive carcinomas of NST for mammographic and sonographic findings compared with 274 nonTN invasive carcinomas of NST Luminal A n 5 189 Reference subtype Mammographic parenchymal pattern ,50%* .50% Mammographic presentation Negative* Mass Calcifications Mass with calcifications Mass margin on mammography Circumscribed* Spiculated Ill-defined Mass margin on US Circumscribed* Indistinct or microlobulated Angular or spiculated Boundary Abrupt* Echogenic halo Internal echogenicity Isoechogenicity* Hypoechogenicity Posterior attenuation No enhancement Enhancement Calcifications None* Microcalcifications

HER-enriched n 5 39

Luminal B n 5 46

OR (95% CI)

p Value

OR (95% CI)

p Value

OR (95% CI)

p Value

1.0 0.567 (0.307–1.050)

0.071

1.0 0.970 (0.416–2.261)

0.943

1.0 0.531 (0.219–1.287)

0.161

1.0 1.249 (0.467–3.340) 0.880 (0.228–3.395) 1.535 (0.514–4.589)

0.657 0.852 0.443

1.0 0.478 (0.053–4.299) 0.119 (0.011–1.323) 0.167 (0.018–1.546)

0.510 0.083 0.115

1.0 2.150 (0.616–7.502) 1.250 (0.221–7.084) 1.000 (0.265–3.769)

0.230 0.801 1.000

1.0 0.134 (0.038–0.473) 1.076 (0.365–3.177)

0.002 0.894

1.0 0.500 (0.088–2.841) 1.7143 (0.369–7.974)

0.434 0.492

1.0 0.077 (0.008–0.758) 0.396 (0.044–3.532)

0.028 0.406

1.0 0.788 (0.211–2.945) 0.360 (0.094–1.377)

0.723 0.136

1.0 0.553 (0.058–5.282) 0.353 (0.036–3.443)

0.607 0.370

1.0 0.477 (0.050–4.534) 0.273 (0.028–2.630)

0.520 0.261

1.0 0.436 (0.241–0.789)

0.006

1.0 0.587 (0.254–1.355)

0.212

1.0 0.548 (0.249–1.203)

0.134

1.0 3.122 (1.570–6.211)

0.001

1.0 1.790 (0.689–4.654)

0.232

1.0 1.964 (0.802–4.807)

0.140

1.0 3.629 (1.627–8.096)

0.002

1.0 1.746 (0.580–5.254)

0.322

1.0 1.773 (0.632–4.975)

0.277

1.0 0.690 (0.359–1.326)

0.265

1.0 0.221 (0.094–0.520)

0.001

1.0 0.449 (0.196–1.030)

0.059

CI 5 confidence interval; NST 5 no special type; TN 5 triple-negative; US 5 ultrasound. * Reference category.

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Ultrasound in Medicine and Biology

Volume 41, Number 2, 2015

Table 3. Odds ratio of 70 TN invasive carcinomas of NST for mammographic and sonographic findings compared with 274 nonTN invasive carcinomas of NST after adjustment of histologic and nuclear grades Luminal A

Mammographic parenchymal pattern ,50%* .50% Mammographic presentation Negative* Mass Calcifications 6 mass Mass margin on mammography Circumscribed* Spiculated Ill-defined Mass margin on US Circumscribed* Indistinct or microlobulated Angular or spiculated Boundary Abrupt* Echogenic halo Internal echogenicity Isoechogenicity* Hypoechogenicity Posterior attenuation No enhancement Enhancement Calcification None* Microcalcification

HER-enriched

Luminal B

OR (95% CI)

p Value

OR (95% CI)

p Value

OR (95% CI)

p Value

1.0 0.667 (0.341–1.306)

0.237

1.0 0.957 (0.408–2.244)

0.919

1.0 0.583 (0.231–1.470)

0.253

1.0 0.760 (0.262–2.202) 0.724 (0.232–2.258)

0.614 0.578

1.0 0.437 (0.048–4.003) 0.144 (0.016–1.326)

0.464 0.087

1.0 1.358 (0.367–5.019) 0.676 (0.174–2.630)

0.646 0.572

1.0 0.219 (0.056–0.847) 1.315 (0.402–4.299)

0.028 0.650

1.0 0.432 (0.074–2.526) 1.652 (0.352–7.746)

0.352 0.525

1.0 0.106 (0.010– 1.114) 0.459 (0.049– 4.343)

0.062 0.497

1.0 1.257 (0.293–5.396)

0.758

1.0 0.574 (0.059–5.552)

0.632

1.0 0.764 (0.073–8.006)

0.822

0.750 (0.170–3.312)

0.704

0.371 (0.037–3.706)

0.398

0.550 (0.051–5.888)

0.621

1.0 0.309 (0.159–0.603)

0.001

1.0 0.588 (0.252–1.375)

0.221

1.0 0.437 (0.189–1.010)

0.053

1.0 2.337 (1.124–4.858)

0.023

1.0 1.750 (0.665–4.604)

0.257

1.0 1.509 (0.597–3.817)

0.385

1.0 2.358 (0.974–5.711)

0.057

1.0 1.656 (0.539–5.086)

0.378

1.0 1.129 (0.373–3.420)

0.830

1.0 0.481 (0.234–0.990)

0.047

1.0 0.213 (0.089–0.511)

0.001

1.0 0.355 (0.146–0.860)

0.022

CI 5 confidence interval; NST 5 no special type; TN 5 triple-negative; US 5 ultrasound. * Reference category.

precancerous stage such as in situ. Krizmanich-Conniff et al. (2012) found that the percentage of masses with circumscribed margins (8%) in their 207 TNBC cases was lower than numbers in previous reports. They suggested that this disparity was due to a different definition of circumscribed margin as well as a relatively large number of patients. In our study, the circumscribed margin was less common than in previous reports. This may have been a result of the strict application of the BI-RADS lexicon because we retrospectively reviewed our cases with information on their malignant pathologic conditions. On US, TN invasive carcinoma of NST most commonly presented as an irregular mass with microlobulated margin, internal hypoechogenicity, an abrupt boundary, no posterior acoustic change and non-parallel orientation and was less likely to have an echogenic halo and calcifications, which was consistent with conclusions found in previous studies (Boisserie-Lacroix et al. 2012; Choi et al. 2011; Dogan et al. 2010; Kojima and Tsunoda 2011; Krizmanich-Conniff et al. 2012; Wang et al. 2008; Wojcinski et al. 2012). Furthermore, posterior acoustic enhancement was more commonly

observed in TNBC compared with non-TNBC (p 5 0.006). This result is supported by TNBCs having a higher grade, being more cellular, being more uniform and being more likely to undergo necrosis and rapid tumor growth (Irshad et al. 2013; Lamb et al. 2000; Shin et al. 2011). Therefore, posterior enhancement was more commonly seen on the US of TNBCs. Additionally, a typical growth pattern (syncytial growth pattern) of TNBC doesn’t tend to make an echogenic halo, which is one of the TNBC characteristics confirmed in both previous studies and ours. Similar to previous reports (Blaichman et al. 2012; Choi et al. 2011; Ko et al. 2010; Krizmanich-Conniff et al. 2012; Wojcinski et al. 2012), TN invasive carcinoma of NST was associated with a high histologic and nuclear grade in this study. After adjustment of histologic and nuclear grades, most characteristics of TNBC were maintained or had more significant differences. So the well-known characteristics of TNBC, such as relative circumscribed margin, less echogenic halo, hypoechogenicity and less calcifications can be considered as unique characteristics of TNBC.

Features of triple-negative breast cancer d H. K. JUNG et al.

There were several limitations in our study. First, there may be observer variability in the interpretation of mammography and US findings. Another limitation is that the number of patients with HER2-enriched and luminal B was relatively small. It seems a trend that their number is often smaller in clinical practice. So, the issue should be considered that their characteristics can be derived from a relatively small number of patients, which may affect our results. We did not analyze the incidence of cases associated with DCIS. Finally, we evaluated the imaging findings of known breast cancer patients without knowledge of cancer subtypes. Thus, we tried to find any suspicious imaging findings associated with cancer, and consequently the cases that were classified as having circumscribed margins seem to be less likely. CONCLUSIONS Compared with non-TNBC, TN invasive carcinoma of NST lacked major suspicious imaging findings such as an irregular shape, spiculated margin and calcifications. The lesion usually presented as a rounded mass with a non-spiculated margin on mammography and an internal hypoechogenicity, abrupt boundary and posterior acoustic enhancement. These imaging features resulted from innate TN characteristics rather than high histologic or nuclear grades. Acknowledgments—This work was supported by the 2013 Inje University research grant.

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