Ultrasound in Med. & Biol., Vol. 40, No. 2, pp. 293–299, 2014 Copyright Ó 2014 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.2013.10.004

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Original Contribution PERIPHERAL ENHANCEMENT OF BREAST CANCERS ON CONTRAST-ENHANCED ULTRASOUND: CORRELATION WITH MICROVESSEL DENSITY AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION HE LIU, YUXIN JIANG, QING DAI, QINGLI ZHU, LIANG WANG, and JIA LU Ultrasound Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China (Received 18 May 2013; revised 25 August 2013; in final form 7 October 2013)

Abstract—There is little evidence of an association between peripheral enhancement on contrast-enhanced ultrasound and histopathologic prognostic factors in breast cancer. The purpose of our study was to investigate the relationship of peripheral enhancement on contrast-enhanced ultrasound with microvessel density, vascular endothelial growth factor (VEGF) expression and other prognostic factors in patients with breast cancer. In 51 patients with BI-RADS (Breast Imaging Reporting and Data System) category 5 lesions scheduled for surgery, contrast-enhanced ultrasound with an 8-4 linear transducer and B-mode pulse inversion harmonic imaging was performed after administration of SonoVue. Forty-three histologically confirmed breast cancers were included in the study and divided into the peripheral enhancement group and non-peripheral enhancement group on the basis of their features on contrast-enhanced ultrasound. The ratio of peripheral to central microvessel density, VEGF expression, tumor size, histopathologic type, stage, lymph node metastasis and expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 were compared between the two groups. The ratio of peripheral to central microvessel density and a peripherally positive/centrally negative VEGF expression pattern were significantly higher in the peripheral enhancement group than in the non-peripheral enhancement group (t-test, p 5 0.023, and c2 test, p 5 0.035, respectively). There were no significant differences in breast cancer size, histopathologic type, stage, lymph node metastasis or expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53 between the two groups (c2 test, p 5 0.416, 0.877, 0.543, 0.124, 0.453, 0.554, 0.350 and 0.479 respectively). The peripheral enhancement pattern of breast cancer on contrast-enhanced ultrasound may be valuable in the evaluation of peripheral/central tumor angiogenesis and VEGF expression. (E-mail: yuxinjiangxh@ yahoo.com.cn) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Breast cancer, Ultrasound contrast, Microvessel density, Vascular endothelial growth factor.

INTRODUCTION

benign and malignant breast lesions, but may also provide valuable information about breast cancer aggressiveness and prognosis. As a measure of tumor angiogenesis, microvessel density (MVD) has been found to correlate with tumor growth and metastasis. Several studies have reported an association between MVD and such prognostic indicators as tumor grade and proliferative activity (Lamuraglia et al. 2005; Szabo et al. 2003; Weidner et al. 1992). Invasive breast carcinomas with higher MVD were associated with more distant metastases and a higher rate of recurrence (Weidner et al. 1992). Vascular endothelial growth factor (VEGF) plays a crucial role in stimulating vascular endothelial cell growth and increasing microvessel permeability. Expression of VEGF and its receptor in breast cancer is associated with many clinical and prognostic factors (Brown et al. 1995; Gasparini et al. 1999; Linderholm et al. 2003). Tumor size, lymph node status and histologic type have

The usefulness of contrast-enhanced ultrasound (CEUS) in differentiation between benign and malignant breast lesions has been reported (Du et al. 2008, 2012; Du et al. 2012; Li et al. 2013; Sorelli et al. 2010; Szabo et al. 2013; Zhao et al. 2010). Our initial study indicated that the peripheral enhancement pattern is suggestive of malignancy, with a diagnostic sensitivity, specificity and accuracy of 39.5%, 98.3% and 73.8%, respectively (Liu et al. 2008). The enhancement is influenced by the extent and pattern of tumor angiogenesis; it is hence reasonable to assume that the enhancement pattern may not only be useful in differentiation between

Address correspondence to: Yuxin Jiang, No. 1 Shuaifuyuan, Dong Cheng District, Beijing 100730, China. E-mail: yuxinjiangxh@ yahoo.com.cn 293

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been used to predict the prognosis of breast cancer (Elston et al. 1999). The absence of estrogen receptor (ER) and progesterone receptor (PR) expression usually indicates a poor prognosis (Yaghan et al. 1998). c-erbB2 and p53 are biomarkers currently used to determine tumor invasiveness and metastatic potential (Bergh 1999; Lovekin et al. 1991). Peripheral rim enhancement on breast contrastenhanced magnetic resonance imaging (MRI) is the most specific feature of breast cancer (Matsubayashi et al. 2000; Teifke et al. 2006). Several studies have reported that peripheral rim enhancement on MRI is associated with larger tumor size, higher histologic grade, ER-negative status, PR-negative status and positive lymph node status (Jinguji et al. 2006; Lee et al. 2008; Szab o et al. 2003; Teifke et al. 2006). CEUS is similar to MRI in that the enhancement is influenced by the extent and pattern of tumor angiogenesis. Our published results indicate that peripheral enhancement is a fairly specific (specificity 98.3%) sign of breast cancer on CEUS, with a positive predictive value of 94.4%. To our knowledge, the role of peripheral enhancement on CEUS is still unclear in the evaluation of the biologic activity of breast cancer. The purpose of our study was to explore the associations between the peripheral enhancement pattern of breast cancer and common histopathologic prognostic factors and to examine whether the peripheral enhancement pattern is useful in predicting tumor biologic activity pre-operatively. METHODS Patients The study design and protocol were approved by the ethics committee of our institution, and written informed consent was obtained. From March 2011 to December 2011, 51 patients with BI-RADS (Breast Imaging Reporting and Data System) category 5 lesions on conventional US underwent pre-operative CEUS. The one inclusion criterion was the presence of lesions on conventional US. Exclusion criteria were contraindications to CEUS, pregnancy or breastfeeding and treatment with neoadjuvant chemotherapy. All final diagnoses of the lesions were based on surgical pathology. Of the 51 patients, 43 had breast cancer, and 8 had benign lesions. The 43 breast cancer patients (age range: 34–70 y, mean age: 50.3 y, median age: 50 y) with complete clinical data constituted the study group. Ultrasound examination An iU22 US (Philips Medical Systems, Bothell, WA, USA) unit with a 12- to 5-MHz linear transducer was used for conventional US. The same unit with an 8to 4-MHz linear transducer and B-mode pulse inversion

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harmonic imaging was used for CEUS. B-Mode pulse inversion harmonic imaging transmits two ultrasound waves with 180 phase inversion and receives the sum of the echoes back from both. It improved the sensitivity to and resolution of the signals produced by microbubbles. All ultrasound examinations were performed by one experienced ultrasound physician (L.H., with 8 y of experience in breast US and 3 y of experience in breast CEUS). The lesion was located and imaged on conventional US. The plane with the richest vascularity was selected for CEUS. The selected plane included the lesion and its surrounding normal tissue, if possible, and remained unchanged during the CEUS examination. The contrast agent used was SonoVue (Bracco, Milan, Italy). It is a lyophilized powder of phospholipidstabilized microbubbles containing sulfur hexafluoride gas with a mean diameter of 2.5 mm; the solution was reconstituted by the addition of 5 mL of sterile saline. CEUS examination was performed immediately after a bolus injection of 2.4 mL of SonoVue via the antecubital vein, and lasted up to 3 min. The machine parameters for CEUS were adjusted so that mechanical index was less than 0.1, the imaging depth was 3 or 4 cm and the single focus zone was at the bottom. In addition, no pressure was exerted on the transducer to avoid weakening the contrast signals. All static and dynamic images were stored in the iU22 system for subsequent analysis. Image analysis All US images were evaluated by two ultrasound physicians (L.H. and Z.Q.L. by consensus), who were blinded to the patients’ clinical data. If disagreement occurred, the two readers jointly reviewed the images, discussed and came to a consensus. The enhancement patterns was classified into three categories based on the distribution of enhanced areas of the lesion (Liu et al. 2008): (i) peripheral enhancement, if enhancement only appeared or was confined predominantly to the periphery of the lesion (Fig. 1); (ii) homogeneous enhancement, if the entire lesion was homogeneously and diffusely enhanced (Fig. 2); (iii) heterogeneous enhancement, if the lesion was heterogeneously enhanced (Fig. 3). If a mixture of enhancement patterns occurred in the same lesion, that lesion was assigned to only one category based on the most prominent enhancement pattern existing in the lesion. Lesions with a peripheral enhancement pattern were included in the peripheral enhancement group, and lesions with a homogeneous or heterogeneous enhancement pattern were included in the non-peripheral enhancement group. Histopathologic analysis All surgical specimens were specifically evaluated by one pathologist (C.X.Y.) with more than 10 y of

Peripheral enhancement of breast cancers on CEUS d H. LIU et al.

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Fig. 1. Surgical pathology confirmed that a palpable mass in the outer upper quadrant of the right breast of a 47-y-old woman was invasive ductal carcinoma. (a) Conventional ultrasound revealed an irregular hypoechoic mass measuring 22 3 18 mm, with peripheral blood flow. (b) Contrast-enhanced ultrasound revealed peripheral enhancement; enhanced areas are confined to the lesion periphery (arrows) and no enhancement is seen in the central area. (c) An immunohistochemically stained section (anti-CD34 stain) revealed a high density of microvessels (brown markings) at the tumor periphery. (d) Another immunohistochemically stained section (anti-VEGF stain) revealed peripherally positive and centrally negative VEGF expression (arrows).

experience in breast pathology. The cancers were histologically typed according to the World Health Organization classification. Lymph node status was recorded as the number of positive lymph nodes among all lymph nodes collected in patients who underwent radical mastectomy. Immunohistochemical staining was performed to identify the following indicators: CD34 (QB-END/10, Novocastra Laboratory, Tokyo, Japan); VEGF (MAB293; R&D Systems, Minneapolis, MN, USA); ER (M0241 [clone 1 D5], Changdao, Shanghai, China); PR (R0448 [clone 1 A6], Changdao); c-erb-B2 (A0485, Dako, Glostrup, Denmark); and p53 (M7001 [clone DO7], Dako). CD34 was used for microvessel quantification. The fields that corresponded to the three most vascularized fields (hot spots) at 340 magnification in the peripheral and central portions were chosen. Microvessels were counted in the three fields at 3200 magnification in both the peripheral and central portions of each lesion. The mean counts of the three fields were recorded as MVD, and ratios of peripheral to central microvessel density were calculated for each lesion. VEGF staining was evaluated according to a previously reported method (Matsubayashi et al. 2000). Staining intensity was classified as 0 5 negative, 1 5 clearly identified at 3100 magni-

fication, and 2 5 clearly identified at a 340 magnification. The areas stained were divided into four grades: 0 5 none of the tumor or epithelial cells was stained; 1 5 one-third or less of the tumor or epithelial cells was stained; 2 5 twothirds or less of the tumor or epithelial cells was stained; and 3 5 two-thirds or more of the tumor or epithelial cells was stained. The staining was considered positive for VEGF when the total score of the stain intensity and quantification measurements was $4. We evaluated VEGF staining in both the peripheral and central areas of each

Fig. 2. Surgical pathology confirmed that a palpable mass in the outer upper quadrant of the left breast of a 45-y-old woman was invasive ductal carcinoma. Contrast-enhanced ultrasound revealed homogeneous enhancement; the entire lesion was homogeneously and diffusely enhanced (arrows).

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1 (2.3%) was mucinous carcinoma and 1 (2.3%) was intraductal papillary carcinoma. The mean size of breast cancers was 2.4 cm (0.5–7.6 cm). Twenty-one (48.8%) were T1 (,2 cm), 18 (41.9%) were T2 (2–5 cm) and 4 (9.3%) were T3 (.5 cm). There were no cases of T4. Lymph node metastases were present in 14 of 43 patients (32.6%). No patient had distant metastases. Fig. 3. Surgical pathology confirmed that a palpable mass in the outer upper quadrant of the left breast of a 43-y-old woman was invasive ductal carcinoma. Contrast-enhanced ultrasound revealed heterogeneous enhancement; the lesion was heterogeneously enhanced (arrows).

lesion. The ER and PR positivity cutoff point was 10%. Staining was considered positive for c-erb-B2 when almost all tumor cells exhibited distinctive membranous staining; it was considered negative when more than 10% of tumor cells exhibited weak to moderate complete membrane staining. p53 expression was considered positive when well-defined nuclear staining was observed. Statistical analysis The SPSS software package (Version 13.0, SPSS Institute, Cary, NC, USA) was used for statistical data analysis. Data were expressed as the mean 6 standard deviation. The t-test was used to determine whether the ratio of peripheral to central microvessel density differed between the peripheral enhancement group and the nonperipheral enhancement group. The c2 test was performed to determine whether VEGF expression, tumor size, histologic type, stage, lymph node metastasis, and expression of ER, PR, c-erbB2 and p53 differed between the peripheral enhancement group and non-peripheral enhancement group. For these tests, a p-value , 0.05 was considered indicative of statistical significance. RESULTS Lesion diagnosis Of the 43 breast cancers, 35 (81.4%) were invasive ductal carcinoma, 3 (7.0%) were ductal carcinoma in situ (DCIS), 3 (7.0%) were invasive lobular carcinoma,

Peripheral enhancement pattern, MVD and VEGF expression The peripheral enhancement pattern was observed in 17 (39.5%) breast cancers, including 15 invasive ductal carcinomas, 1 invasive lobular carcinoma and 1 mucinous carcinoma. Heterogeneous enhancement was observed in 19 (44.2%) cases, including 15 invasive ductal carcinomas, 2 invasive lobular carcinomas, 1 DCIS and 1 intraductal papillary carcinoma. Homogeneous enhancement was observed in 7 (16.3%) cases, including 5 invasive carcinomas and 2 DCISs. Seventeen (39.5%) breast cancers were included in the peripheral enhancement group, and 26 (60.5%) breast cancers in the nonperipheral enhancement group. The ratio of peripheral to central microvessel density was significantly higher in the peripheral enhancement group (1.73 6 0.58) than in the non-peripheral enhancement group (1.28 6 0.35) (t-test, p 5 0.023) (Table 1). Peripherally positive/centrally negative VEGF expression was significantly higher in the peripheral enhancement group (8 cases, 47%) than in the non-peripheral enhancement group (3 cases, 13%) (c2-test, p 5 0.035) (Table 2). Peripheral enhancement pattern and prognostic factors There were no significant differences in breast cancer size, histopathologic type, stage or lymph node metastasis between the peripheral and non-peripheral enhancement groups (c2-test, p 5 0.416, 0.877, 0.543 and 0.124, respectively) (Table 3). No significant difference was found in expression of ER, PR, C-erb-B2 and p53 between the peripheral and non-peripheral enhancement groups (c2-test, p 5 0.453, 0.554, 0.350 and 0.479, respectively) (Table 4).

Table 1. Comparison of peripheral and non-peripheral enhancement groups with respect to peripheral/central microvessel density ratio Microvessel density Mean

Range

Enhancement group

Periphery

Center

Periphery/center

Periphery

Center

Peripheral Non-peripheral

48 6 18 47 6 15

29 6 10 38 6 12

1.73 6 0.58* 1.28 6 0.35*

25–75 13–80

10–61 15–80

* t-test, p 5 0.023.

Peripheral enhancement of breast cancers on CEUS d H. LIU et al.

Table 2. Comparison of peripheral and non-peripheral enhancement groups with respect to VEGF expression* Periphery/center VEGF expression 1/– 1/1 –/1 –/–

Peripheral enhancement

Non-peripheral enhancementy

8 (47%) 3 (18%) 0 (0) 6 (35%)

3 (13%) 11 (48%) 0 (0) 9 (39%)

p-value

0.035

VEGF 5 vascular endothelial growth factor. * c2-test, p 5 0.035. y Two ductal carcinomas in situ and one invasive ductal carcinoma were excluded because of missing histologic slides.

DISCUSSION Recently, CEUS has been playing an important part in the detection and estimation of the extent of breast cancer. Although several studies have assessed the usefulness of CEUS in breast cancer diagnosis, few studies have examined the correlation of enhancement characteristics with prognostic factors (Du et al. 2008, 2012; Du et al. 2012; Sorelli et al. 2010; Wang et al. 2011; Zhao et al. 2010). One study has reported that perfusion defect, radial or penetrating vessels and hyper-enhancement are associated with breast cancer prognosis (Wan et al. 2012b). Another study found that increased tumor perfusion, which manifests as faster wash-in and accelerated wash-out, appears to indicate a worse prognosis in invasive breast cancer (Szab o et al. 2013). However, to our knowledge, no studies have investigated the relationship of MVD, VEGF and prognostic factors to the peripheral enhancement pattern on CEUS, which is specific to breast cancers as described previously (Liu et al. 2008). In agreement with findings of Matsubayashi et al. (2000), we found a higher ratio of peripheral to central Table 3. Comparison of peripheral and non-peripheral enhancement groups with respect to breast cancer size, histopathologic type, stage and lymph node metastasis*

Tumor size #2 .2 Histologic type Ductal carcinoma in situ Invasive cancery Lymph node metastasis – 1 Clinical stage 0 I II III

Peripheral enhancement

Non-peripheral enhancement

p-value

7 10

14 12

0.416

0 17

4 22

0.877

12 5

16 10

0.543

0 5 8 4

4 10 7 5

0.124

* c2-test, p 5 0.416, 0.877, 0.543 and 0.124, respectively. y Invasive cancer includes 35 invasive ductal carcinomas, 3 invasive lobular carcinomas and 1 medullary carcinoma.

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Table 4. Comparison of peripheral and non-peripheral enhancement groups with respect to expression of estrogen receptor, progesterone receptor, c-erb-B2 and p53

Estrogen receptor 1 – Progesterone receptor 1 – c-erb-B2 1 – p53 1 –

Peripheral enhancement

Non-peripheral enhancement

p-value

7 10

9 17

0.453

7 10

10 16

0.554

6 11

12 14

0.350

1 16

3 23

0.479

microvessel density and peripherally positive/centrally negative VEGF expression in the peripheral enhancement group than in the non-peripheral enhancement group. The results suggest that the peripheral enhancement pattern may reflect the density and distribution of the lesion’s microvessels and VEGF expression. No significant difference was found in breast cancer size, histopathologic type, stage, lymph node metastasis or expression of ER, PR, c-erb-B2 and p53 between the peripheral and nonperipheral enhancement groups. Owing to the lack of relevant research in the field of CEUS, we can only compare our findings with those of studies that focused on the prognostic value of MRI-detected peripheral rim enhancement. Several studies have reported that peripheral rim enhancement on MRI is associated with larger tumor size, higher histologic grade, ER-negative status, PR-negative status and positive lymph node status (Jinguji et al. 2006; Lee et al. 2008; Szabo et al. 2003; Teifke et al. 2006). These results differ from the results of our study. The precise reason for this discrepancy is unknown. It may be due to the small sample size or, more importantly, the different imaging principles and analysis methods of CEUS and MRI. First, US contrast medium is strictly intravascular, and the enhancement signals come only from blood vessels. MRI contrast agent is intravascular and extracellular in distribution; therefore, the enhancement is influenced by vessel density, capillary permeability, interstitial component pressure and other factors (Matsubayashi et al. 2000; Teifke et al. 2006). Second, peripheral enhancement on ultrasound is identified at the point of maximal enhancement, without considering the dynamic change in contrast agent during the wash-in and wash-out phases, whereas peripheral rim enhancement on MRI includes: (i) early rim enhancement followed by little change in the delayed phase; (ii) early rim enhancement followed

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by progressive central filling of contrast medium in the delayed phase; and (iii) delayed rim enhancement as a result of central wash-out of contrast medium. Early peripheral enhancement followed by centripetal progression or delayed peripheral enhancement as a result of central wash-out of contrast medium may be classified as heterogeneous or homogeneous enhancement instead of peripheral enhancement on ultrasound. Therefore, CEUS-detected peripheral enhancement and MRIdetected peripheral enhancement are concepts essentially distinct from each other. MRI-detected peripheral enhancement has proven its value in previous studies, whereas little is known about CEUS-detected peripheral enhancement. Further imaging analysis and large-scale studies are needed to reveal its clinical significance. Our study had some limitations. First, it is difficult for the ‘‘most vascular’’ plane on contrast-enhanced ultrasound to be located and marked on the specimen for correct alignment. The ‘‘most vascular’’ plane on contrast-enhanced ultrasound was selected according to the published literature; however, there were no detailed descriptions of how to align the surgical/pathology planes (Du et al. 2008; Wan et al. 2012a). We hypothesize that the histopathologic characteristics of the tumor periphery and central area remain almost unchanged in different pathologic cut faces. Therefore, microvessel density and VEGF expression in the tumor periphery and central area were compared between the peripheral and non-peripheral enhancement groups. Second, only the peripheral enhancement pattern was evaluated in our study. Additional studies that include heterogeneous and homogeneous enhancement may be useful. Third, because of the relatively small sample size, the correlation between CEUS features and prognostic factors could not be thoroughly investigated, and VEGF expression (positive or negative), rather than numerical values, was chosen for data processing and statistical analysis. Fourth, the time-intensity curve obtained from the region of interest by special software was not applied. The time-intensity curve should be objective; however, there is great overlap between malignant and benign breast lesions (Du et al. 2012; Wan et al. 2012b). Fifth, classification of the enhancement patterns was performed visually by two radiologists in consensus; therefore, inter-observer variability could not be evaluated. CONCLUSIONS The peripheral enhancement pattern of breast cancer on CEUS may be valuable in the evaluation of peripheral/ central tumor angiogenesis and VEGF expression. In contrast to MRI results, peripheral enhancement was not found to be associated with histopathologic

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prognostic factors in our study; therefore, CEUSdetected peripheral enhancement may not be used to stage breast cancer. However, the discrepancy between the two imaging modalities warrants further studies to reveal the potentially unique value of CEUS. Acknowledgments—The research was supported by the National Natural Sciences Foundation of China (30900372).

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Peripheral enhancement of breast cancers on contrast-enhanced ultrasound: correlation with microvessel density and vascular endothelial growth factor expression.

There is little evidence of an association between peripheral enhancement on contrast-enhanced ultrasound and histopathologic prognostic factors in br...
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