Complex cystic and solid breast lesions: Diagnostic performance of conventional ultrasound,strain imaging and point shear wave speed measurement

Abstract

OBJECTIVE:

To assess the performance of conventional high frequency ultrasound (US) and US elastography in diagnosis of complex cystic and solid breast lesions.

METHODS:

Ninety three lesions in 93 patients underwent conventional US and US elastography, including strain elastography, acoustic radiation force impulse (ARFI) imaging, and point shear wave speed (SWS) measurement.

RESULTS:

Pathological examination revealed 31 (33.3%) of the 93 lesions were malignant and the remaining 62 (66.7%) were benign. Multivariate analysis showed that elder patient (OR: 25.301), internal vascularity (OR: 4.518), and not circumscribed margin (OR: 3.813) were independent predictors for malignancy, while predominately cystic lesions (OR: 0.178) was a predictor for benign lesions (all p < 0.05). Invalid SWS measurement was occurred in 19 of 31 (61.3%) malignant lesions and 16 of 62 (25.8%) benign lesions, respectively (p < 0.05). The mean SWS value for malignant lesions was significantly lower than that for benign ones, being 1.60±0.63 m/s (range, 0.68–2.70 m/s) versus 2.33±0.77 m/s (range, 0.67–3.97 m/s) (p < 0.05). Areas under the ROC curve (Azs) for Breast Imaging Reporting and Data System (BI-RADS) assessment, strain elasticity score, ARFI imaging and valid point SWS measurement were 0.844, 0.734, 0.763 and 0.778,respectively.

CONCLUSIONS:

US BI-RADS category, strain elastography score, ARFI imaging patterns and point SWS measurement are useful for malignancy prediction of complex cystic and solid breast lesions. The result that SWS for malignant lesions is lower than benign one should be carefully interpreted since invalid SWS measurement is excluded for analysis. The true stiffness of malignant cystic and solid lesions should be further evaluated with a new generation of two-dimensional SWS imaging.

Keywords

Complex cystic and solid lesion breast ultrasound elastography Breast Imaging Reporting and Data System acoustic radiation force impulse

1 Introduction

Breast cancer is a leading threat for women globally due to the high incidence and mortality. Conventional ultrasound (US) is widely used in breast cancer prediction for its cost-effectiveness, no radiation, and high sensitivity [1]. Up to different national conditions, the optimized choice for familiar breast cancer is quite different between Chinese and western health care system. In China, screening breast US combined with mammography is the most economic and optimized choice for familiar breast cancer while mammography combined with adjunctive magnetic resonance imaging (MRI) is the most optimized recommendation for western countries, which make the current study much more meaningful in China. In decades, shape, orientation, margin, echo pattern, posterior acoustic shadowing and accompanied changes were involved as conventional US features for malignancy prediction [2]. By applying American College of Radiology (ACR) US Breast Imaging Report and Data System (BI-RADS) [2], a sensitivity range of 71.2% – 100% and a specificity range of 7.1% – 98.8% have been documented for diagnosis of solid breast lesions when using conventional US alone [1 , 4]. However, little is known for diagnosis of complex cystic and solid breast lesions by using US. The term “complex cystic and solid” has been defined as a combination of cystic/fluid and solid components on US according to ACR BI-RADS lexicon [2]. Besides, it also refers to cystic lesions which contain thick walls or thick septations [5 –7]. Different authors have reported the malignancy rates in a broad spectrum of 10–62.3% in a variety of ways [5 –10]. Conventional US, fortunately, has been gifted an advantage in distinguishing cystic lesions from solid lesions in comparison with mammography, whereas the positive predictive value (PPV) for malignancy prediction is low (6.5–8.9%) [3 , 11].

Recently, US elastography has been introduced into clinical practice to evaluate tissue stiffness. The diagnostic efficacy for solid breast lesions has been confirmed by numeral studies [12 –18]. There are two types of US elastography techniques classified by different imaging principles: strain imaging and shear wave imaging. The former includes strain elastography and acoustic radiation force impulse (ARFI) imaging. The latter includes point shear wave speed (pSWS) measurement, SWS imaging, and transient elastography [19]. Without sacrificing sensitivity, US elastography has achieved a sensitivity range of 70.1% – 100% and a specificity range of 41% – 98.5% in diagnosing solid breast lesions[12 , 20]. Improved diagnostic efficiencies, typically associated with accuracy, sensitivity and specificity, have been extensively reported with combination of conventional US and elastography [10 , 15–17]. Though the potential ability of US elastography to distinguish solid from cystic lesions has been noticed in a previous study [8], few studies evaluate the usefulness of US elastography in diagnosis of complex cystic and solid breast lesions. The diagnostic performance of US elastography for those lesions is still unclear, and might be far different from that in solid breast lesions. Therefore, the present study was aimed to assess the usefulness of conventional US and US elastography in diagnosis of complex cystic and solid breast lesions. Also, the possible associated factors were analyzed.

2 Materials and methods

2.1 Patients

This retrospective study was approved by the Institutional Review Board of the university hospital and oral informed consents were obtained from all patients to include their data for analyses. All the operations were rational according to the ethical guidelines [21]. From July 2013 to January 2016, one hundred and two complex cystic and solid breast lesions in 102 patients were retrieved from the medical record in the institution and all the lesions were confirmed by pathological examination. All of them had underwent conventional US and US elastography assessment before being pathologically confirmed (i.e. US-guided core needle biopsy (CNB) or surgery). The eligibility criteria were listed as follows: [1] Complex cystic and solid lesion according to ACR BIRADS [2]. The lesion had not been treated before by ablation, biopsy or chemotherapy [3]. The maximal diameter of solid portion in the lesion should be greater than 5 mm, because of the unadjustable size of the region of interest (ROI) in point SWS measurement (i.e. 6×5 mm) [4]. Females [5]. Lesions should be pathologically originated from mammary gland. Finally, nine lesions in 9 patients were excluded for the following reasons: [1] Prior therapeutic history (n = 2); [2] The maximal diameter of solid portion were less than 5 mm (n = 5); [3] Male patient (n = 1); [4] Lesion was pathologically originated from other tissue (n = 1). Finally, ninety three lesions in 93 women (median age, 45 years; range, 19–88 years) were enrolled. The flowchart for the lesion selection is present in Fig. 1. Clinical information was retrospectively reviewed from patients’ medical records. For patients with multiple lesions, the most suspicious one or the largest one was included foranalyses.

Fig.1

The enrollment flowchart of the complex cystic and solid breast lesions

2.2 Conventional US and US elastography

All patients were scanned in the supine position by Siemens S2000 US instrument (Siemens Medical Solutions, Mountain View, CA, USA). The probes with 18L6 linear array transducer (frequency range, 7–17 MHz) and 9L4 linear array transducer (frequency range, 4–9 MHz) were used for conventional US examination, while for US elastography, the 9L4 linear array transducer was applied. Bilateral whole breast US examinations were performed by one of three skillful investigators. Sufficient gel was applied to ensure enough contact between the transducer and the skin. The machine settings were optimized to obtain high-quality gray scale and color Doppler US images of the target lesion. Maximal diameters of lesions were all measured on the maximal crosssection.

Subsequently, strain elastography (SE) (i.e. elasticity imaging, EI), ARFI imaging (i.e. Virtual touch tissue imaging, VTI) and point SWS measurement (i.e. Virtual touch tissue quantification, VTQ) were carried out on the basis of related guidelines [19, 22]. With regard to SE examination, tissue stiffness was reflected by lesion deformation after an externally manual pressure. The transducer was perpendicular to the body surface and the patient was asked to hold the breath for a few seconds. The target lesion was placed on the center of the screen. A continuous compression and decompression maneuver with slight pressure from the transducer was applied and continuous scanning of the target lesion was performed for approximately 10 seconds until the image was frozen. With the quality factor (QF) value higher than 60 over several frames, a SE image with high quality was indicated and stored. The SE image was obtained as a color-coded map, with red indicating soft tissue while blue indicating hard tissue.

ARFI imaging and point SWS measurement were then performed. Once ARFI procedure starts, longitudinal tissue displacement and transverse shear wave propagation will be arisen due to the mechanical excitation by short-duration acoustic pulses from the transducer, and the information of tissue deformation and shear wave speed would be denoted by ARFI imaging and point SWS measurement respectively. For ARFI imaging, the target lesion was interrogated for elastic property through a sampling box with the whole lesion and adequate surrounding breast tissue covered. The ARFI imaging was coded by bright and dark area, which was displayed simultaneously in a double-screen mode with the corresponding gray scale image. For point SWS measurement, the stiffness of solid portion in the lesion was quantitatively interrogated with a fixing ROI (i.e. 6 mm×5 mm). The principles for ROI placement were as follows [1]. The ROI should be placed on the solid portion of the lesion [2]. Liquefaction and macrocalcification should be avoided [3]. The adjacent tissue should be avoided. To increase the reliability of measures, point SWS measurement was repeated 7 times for each lesion without movement of the transducer. Between each measurement, a cool-down period (around 2–3 seconds) is necessary [23]. The whole procedure costs about 10 minutes for each patient.

2.3 Data analysis

All images were retrospectively analyzed at the same setting by two readers in a blind manner independently. The final assessment would be decided by a third reader in case of any discordance. Pathological results were unavailable to all the readers. Complex cystic and solid lesions were categorized into predominantly solid (cystic portion <50%) and predominantly cystic (cystic portion ≥50%). Lesion features associated with the description of the breast lesion in ACR BI-RADS lexicon were shape, orientation, margin, echo pattern, posterior acoustic features, internal vascularity, internal calcification. Final BI-RADS assessments for each lesion were determined and recorded according to the ACR BI-RADS lexicon.

For SE, the solid portion was scaled by stain elasticity score (Tsukuba score) [14], which was a five-point scale that visually ranked the stiffness (Fig. 2). Score 1: the entire lesion is shaded in green. Score 2: A mixed pattern of green and blue is visible inside lesion. Score 3: Blue occupies the most of lesion, but not the whole. Score 4: The entire lesion is blue, but surrounding tissue is not involved. Score 5: The entire lesion is blue, and surrounding tissue is involved. The higher score indicates the stiffer tissue.

Fig.2

Images present general appearance of lesions for strain elasticity score (Tsukuba score). (a) Score 1: the entire lesion is shaded in green. (b) Score 2: A mixed pattern of green and blue is visible inside lesion. (c) Score 3: Blue occupies the most of lesion, but not the whole. (d) Score 4: The entire lesion is blue, but surrounding tissue is not involved. (e) Score 5: The entire lesion is blue, and surrounding tissue is involved.

In ARFI imaging, a classification by Tozaki, et al. was applied (Fig. 3) [10]. In point SWS measurement, the highest and the lowest value were eliminated and the mean of the rest 5 measurements were calculated and used in the analysis. Invalid SWS value of “X.XX m/s” was encountered sometimes, which might be caused by multi-factors, such as maximum lesion diameter [24, 25], depth, thickness [26], cystic portion [8], or out of range (0.5–8.4 m/s by default [25]).

Fig.3

Images present general appearance of lesions for AFRI imaging patterns. (a) Pattern 1: Neither bright nor dark area is found inside the lesion (i.e. the entire target region appears grey). (b) Pattern 2: A bright area appears on the target region. (c) Pattern 3: The lesion shows a mixed pattern of bright and dark area, including dark septations and dark rim. (d) Pattern 4a: Darkness occupies the most of lesion, but not the whole. (e) Pattern 4b: Darkness occupies the entire lesion, and surrounding tissue is involved.

2.4 Intra- and Inter-observer reproducibility

To investigate the intraobserver reproducibility, SE and ARFI imaging were respectively reviewed and assessed in 30 patients by the same reader. Interobserver reproducibility was investigated by two independent readers in another 30 patients and both of them had similar experiences in these techniques.

2.5 Statistical analysis

The statistical analyses were carried out using SPSS software package (Version 22.0; SPSS Inc, Chicago, IL). Two-tailed p < 0.05 were considered to be statistically significant. Qualitative data were analyzed with Chi-square test. A multivariate logistic regression analysis was then used to evaluate the malignancy risk for independent variables, and odds ratios (ORs) and 95% confidence intervals (95% CIs) for each feature were calculated. The differences of SWS between benign and malignant lesions were analyzed by independent t test. Receivers operating characteristic (ROC) curve was plotted to evaluate the diagnostic performances of ACR BI-RADS category, SE, ARFI imaging and point SWS measurement in differentiating malignant from benign lesion. Areas under the receiver operating characteristic curves (Az) were calculated and were compared by z test. The diagnostic efficacies were proposed as none (0≤Az≤0.5), low (0.5<Az≤0.7), moderate (0.7<Az≤0.9), and high (Az>0.9). Pearson correlation coefficient was applied to evaluate the intra- and inter-observerreproducibilities.

3 Results

3.1 Basic characteristics

Of the 93 lesions, thirty one (33.3%) were malignant and 62 (66.7%) were benign. In concordance with the World Health Organization (WHO) Classification of Tumours of the Breast, the pathological results of these 93 lesions are illuminated in Table 1. Intraductal papilloma with atypical hyperplasia and boundary phyllodes tumor were regarded as benign lesions in our study for their less invasiveness.

Table 1
Pathological distribution of the 93 breast lesions

Benign n Malignant n

Adenosis 20 (7) Invasive ductal carcinoma 17 (14)

Intraductal papilloma 17 (3) Mucinous carcinoma 5 (2)

Fibroadenoma 14 (2) Ductal carcinoma in situ 3 (1)

Inflammation^* 7 (2) Solid papillary carcinoma 3 (1)

Boundary phyllodes tumor 1 (0) Intraductal papillary carcinoma 2 (1)

Intraductal papilloma with atypical hyperplasia 1 (0) Malignant phyllodes tumor 1 (0)

Pseudoangiomalous stromal hyperplasia 1 (0)

Stromal fibrosis 1 (0)

Total 62 (16) 31 (19)

Benign	n	Malignant	n
Adenosis	20 (7)	Invasive ductal carcinoma	17 (14)
Intraductal papilloma	17 (3)	Mucinous carcinoma	5 (2)
Fibroadenoma	14 (2)	Ductal carcinoma in situ	3 (1)
Inflammation^*	7 (2)	Solid papillary carcinoma	3 (1)
Boundary phyllodes tumor	1 (0)	Intraductal papillary carcinoma	2 (1)
Intraductal papilloma with atypical hyperplasia	1 (0)	Malignant phyllodes tumor	1 (0)
Pseudoangiomalous stromal hyperplasia	1 (0)
Stromal fibrosis	1 (0)
Total	62 (16)		31 (19)

^*Inflammation: Granulomatous inflammation, Abscess, Acute on chronic inflammation. n numbers. Numbers in parentheses indicate the numbers of lesions without valid SWS measurement results on VTQ (i.e. X.XX m/s).

3.2 Conventional US

The malignant lesions were more frequently to be found in elder (i.e.≥40 yrs) patients (30/70, 42.9%) than in younger (i.e.<40 yrs) patients (1/23, 4.30% , p < 0.05). The malignancy rates among large size (i.e.≥20 mm) group (19/39, 48.70%), medium size (i.e.10–19 mm) group (11/40, 27.50%) and small size (i.e.<10 mm) group (1/14, 7.10%) were statistically different (p < 0.05). The malignancy rate significantly declined when the amount of cystic portion increased, from 44.4% (28/63) in predominantly solid lesions to 10.0% (3/30) in predominantly cystic lesions (p < 0.05)(Table 2, Fig. 4).

Table 2
Basic characteristics of the patients and ultrasound features of the lesions

Characteristics Benign (n = 62) Malignant (n = 31) p value

Patient

Age (yrs) 0.001^*

<40 22 1

≥40 40 30

Lesion

Size (mm) 0.011^*

<10 13 1

≥10,<20 29 11

≥20 20 19

Cystic portion (%) 0.001^*

<50% 35 28

≥50% 27 3

Lesion shape 0.004^*

Oval 30 4

Round 2 2

Irregular 30 25

Orientation 0.234

Parallel 49 21

Not parallel 13 10

Margin 0.000^*

Circumscribed 40 6

Not circumscribed 22 25

Echo pattern of solid portion 0.041^*

Hyperechoic 2 0

Isoechoic 9 0

Hypoechoic 44 23

Heterogeneous 7 8

Posterior acoustic features 0.431

Shadowing 3 3

No posterior acoustic features 23 8

Enhancement 36 20

Internal vascularity 0.001^*

Absence 38 8

Presence 24 23

Internal calcification 0.078

Absence 58 25

Presence 4 6

Characteristics	Benign (n = 62)	Malignant (n = 31)	p value
Patient
Age (yrs)			0.001^*
<40	22	1
≥40	40	30
Lesion
Size (mm)			0.011^*
<10	13	1
≥10,<20	29	11
≥20	20	19
Cystic portion (%)			0.001^*
<50%	35	28
≥50%	27	3
Lesion shape			0.004^*
Oval	30	4
Round	2	2
Irregular	30	25
Orientation			0.234
Parallel	49	21
Not parallel	13	10
Margin			0.000^*
Circumscribed	40	6
Not circumscribed	22	25
Echo pattern of solid portion			0.041^*
Hyperechoic	2	0
Isoechoic	9	0
Hypoechoic	44	23
Heterogeneous	7	8
Posterior acoustic features			0.431
Shadowing	3	3
No posterior acoustic features	23	8
Enhancement	36	20
Internal vascularity			0.001^*
Absence	38	8
Presence	24	23
Internal calcification			0.078
Absence	58	25
Presence	4	6

^*indicates statistically significant difference.

Fig.4

Images in a 58-years-old woman with intraductal papillary carcinoma. (a) and (b), at conventional US, an 19-mm breast lesion at 10 o’clock position of the right breast appears to be predominately solid, oval in shape, parallel in orientation, circumscribed in margin, hypoechogenicity, enhancement in posterior acoustic features, absence of internal vascularity and calcification, and is finally classified as BI-RADS category 4a. At elastography, SE score of 3 (c), ARFI imaging pattern 2 (d), and SWS of 1.14 m/s (e) are found. (f) Histologic specimen (hematoxylin-eosin stain; original magnification,×200) confirms a diagnosis of intraductal papillary carcinoma.

US features such as shape, margin, echo pattern, and vascularity were significantly involved in the nature of complex cystic and solid breast lesions (all p < 0.05) (Table 2). By multivariate logistic regression analysis, patient age (OR: 25.301; 95% CI: 2.832, 226.062) was the strongest independent predictor for malignancy, followed by vascularity (OR: 4.518; 95% CI: 1.405, 14.526) and margin (OR: 3.813; 95% CI: 1.090, 13.334). And cystic portion was an independent protective factor for lesions (OR: 0.178; 95% CI: 0.038, 0.824) (all p < 0.05) (Table 3, Fig. 4).

Table 3

Multivariate logistic regression analysis for basic and US characteristics

Characteristics	β	SE	OR	95% CI	p value
Patient age	3.231	1.117	25.301	2.832–226.062	0.004^*
Cystic portion	–1.726	0.782	0.178	0.038–0.824	0.027^*
Margin	1.338	0.639	3.813	1.090–13.334	0.036^*
Vascularity	1.508	0.596	4.518	1.405–14.526	0.011^*

β, regression coefficient, SE, standard error, OR, odds ratio; CIs, Confidence intervals. ^*indicates statistically significant difference.

The associated Az was 0.844 (95% CI: 0.756, 0. 932) for malignancy prediction with BI-RADS category. With a cutoff point between BI-RADS 3 and 4a category, the sensitivity, specificity, PPV, NPV and accuracy were 96.8% , 33.9% , 42.3% , 95.5% and 54.8% , respectively (Table 4).

Table 4

The diagnostic performance of US BI-RADS, SE, ARFI elastography for malignancy prediction

Methods	Optimized cut-off value	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)	Az (95% CIs)
US BI-RADS	≥Category 4a	96.8 (30/31)^a	33.9 (21/62)^a	42.3 (30/71)	95.5 (21/22)^a	54.8 (51/93)	0.844 (0.756–0.932)
SE	Score≥4	51.6 (16/31)	79.0 (49/62)	55.2 (16/29)	76.6 (49/64)	69.9 (65/93)	0.734 (0.627–0.840)
ARFI imaging	Score≥4	58.1 (18/31)	80.7 (50/62)	60.0 (18/30)	79.3 (50/63)	73.1 (68/93)	0.763 (0.657–0.868)
point SWS measurement	<2.28 m/s	91.7 (11/12)	54.3 (25/46)	34.4 (11/32)	96.2 (25/26)	62.1 (36/58)	0.778 (0.639–0.917)

US, ultrasound; BI-RADS, Breast Imaging Reporting and Data System; SE, strain elastography; ARFI, Acoustic Radiation Force Impulse; SWS, point shear wave speed, PPV positive predictive value; NPV negative predictive value; Az, Area under the curve; CIs confidence intervals. ^ap < 0.05 in comparison with SE, ARFI imaging.

3.3 US elastography findings

SE and ARFI imaging results were obtained from 93 lesions. Valid SWS values were obtained from 58 lesions therein and the pathological distribution of remained 35 lesions occurred with “X.XX m/s” was also present in Table 1 and Fig. 5. Detailed ROC curve analyses for strain elasticity score and AFRI imaging patterns in all the 93 lesions are present in Fig. 6, and the associated Az, sensitivity, specificity, PPV, NPV and accuracy are present in Table 4. The SWS value for malignant lesions was significantly lower than that for benign ones, being 1.60±0.63 m/s (range, 0.68–2.70 m/s) versus 2.33±0.77 m/s (range, 0.67–3.97 m/s) (p < 0.05) (Figs. 4 and 7). Comparing with the associated Azs of BI-RADS, SE, ARFI imaging and point SWS measurement, there were no statistical differences between any two of them (all p≥0.05). Overall, BI-RADS category, strain elasticity score, AFRI imaging patterns and point SWS measurement were illuminated to be useful for malignancy prediction (all p < 0.05, Table 5).

Fig.5

Images in a 59-years-old woman with invasive ductal carcinoma. (a) and (b), at conventional US, an 18-mm breast lesion at 3 o’clock position of the left breast appears to be predominately solid, oval in shape, parallel in orientation, not circumscribed in margin, hypoechogenicity, enhancement in posterior acoustic features, present of internal vascularity, absence of calcification, and is finally classified as BI-RADS category 4b. At elastography, SE score of 4 (c), ARFI imaging pattern 4b (d), and SWS of “X.XX” m/s (e) are occurred. (f) Histologic specimen (hematoxylin-eosin stain; original magnification,×200) confirms a diagnosis of invasive ductal carcinoma.

Fig.6

Receiver operating characteristic (ROC) curves for Breast Imaging Reporting and Data System (BI-RADS) assessment, acoustic radiation force impulse (ARFI) imaging pattern and strain elasticity score (Tsukuba score). Area under the curve (Az) for them are 0.844 (95% CI, 0.756–0.932), 0.763 (95% CI, 0.657–0.868) and 0.734 (95% CI, 0.627–0.840), respectively.

Fig.7

Box-and-whisker plots for shear wave speed (SWS) value (m/s). The bottom and top of the boxes indicate 25th and 75th percentiles of the values, respectively. The horizontal line inside the box indicates median values. The dashed horizontal line (2.28 m/s) indicates optimized cutoff value of SWS values.

Table 5

Conventional ultrasound and ultrasound elastography between malignant and benign lesions

Methods	Benign, n	Malignant, n	p value
BIRADS category			<0.001^*
2 (n = 1)	1 (100.0%)	0 (0%)
3 (n = 21)	20 (95.2%)	1 (4.8%)
4a (n = 43)	34 (79.1%)	9 (20.9%)
4b (n = 13)	6 (46.2%)	7 (53.8%)
4c (n = 10)	1 (10.0%)	9 (90.0%)
5 (n = 5)	0 (0%)	5 (100.0%)
Total (n = 93)	62 (66.7%)	31 (33.3%)
SE			0.001^*
1 (n = 10)	10 (100.0%)	0 (0%)
2 (n = 22)	18 (78.3%)	5 (21.7%)
3 (n = 31)	21 (67.7%)	10 (32.3%)
4 (n = 18)	11 (61.1%)	7 (38.9%)
5 (n = 11)	2 (18.2%)	9 (81.8%)
Total (n = 93)	62 (66.7%)	31 (33.3%)
ARFI imaging patterns			<0.001^*
1 (n = 16)	15 (93.8%)	1 (6.3%)
2 (n = 28)	21 (75.0%)	7 (25.0%)
3 (n = 19)	14 (73.7%)	5 (26.3%)
4a (n = 18)	11 (61.1%)	7 (38.9%)
4b (n = 12)	1 (8.3%)	11 (91.7%)
Total (n = 93)	62 (66.7%)	31 (33.3%)
Valid point SWS measurement			0.004^*
SWS≤2.28 m/s (n = 32)	21 (65.6%)	11 (34.4%)
SWS>2.28 m/s (n = 26)	25 (96.2%)	1 (3.8%)
Total (n = 58)	46 (79.3%)	12 (20.7%)
Valid/Invalid SWS			0.001^*
Invalid point SWS measurement (n = 35)	16 (45.7%)	19 (54.3%)
Valid point SWS measurement (n = 58)	46 (79.3%)	12 (20.7%)
Total (n = 93)	62 (66.7%)	31 (33.3%)

^*indicates statistically significant difference at the level of two-tailed 0.05. Numbers in parentheses are percentages. n, number; SE, strain elasticity; ARFI imaging, acoustic radiation force impulse imaging; SWS, shear wave speed.

3.4 Intra- and inter-observer reproducibilities

The correlation coefficient value were 0.904 and 0.887 for intraobserver in strain elasticity score and ARFI imaging patterns, and 0.864 and 0.869 for interobserver (both p < 0.05).

4 Discussion

In the current study, US is demonstrated to be an efficient approach in malignancy prediction for complex cystic and solid breast lesions with an associated Az of 0.844 for BI-RADS. Patient age is revealed to be the strongest independent predictor for malignancy in complex cystic and solid breast lesions (OR: 25.301), followed by vascularity (OR: 4.518) and margin (OR: 3.813). Moreover, in highly agreement with researches from Berg et al. and Omori et al. [9, 27], the cystic portion is inversely related to the malignancy risk in complex cystic and solid breast lesions (OR: 0.178), which has contributed majorly to being a benign lesion.

It is acknowledged that the distribution of patient age is significant different in breast cancer. As Booi et al. found in cystic breast lesions, the mean patient age in malignancy was significantly higher than that in benign lesions [8]. The decision made on cutoff point of patient age (40 yrs) referred in our study was based upon the significance of further exams (e.g. mammography) or treatments [28]. The risk of being malignancy in complex cystic and solid breast lesions is around 25 times in older patients (≥40 yrs) as that in younger patients (<40 yrs) (OR: 25.301).

In our study, internal vascularity was illuminated to be a key indicator to malignancy in complex cystic and solid lesions (OR: 4.518). Sehgal et al. also reported that around 14% – 54% more vascular were found in malignancy [29]. On the other hand, among the lesions without any internal vascularity,38 (82.6%) lesions were pathologically identified to be benignity in the current study. In addition, irregular margin showed an OR value of 3.89 to malignancy in complex cystic and solid breast lesions which might be explained by the infiltrative tumor cells or aggressivity associated with invasive component [30]. Berg, et al. reported that the irregular margin, including angular, indistinct and microlobulated, and thick walls could frequently been found in malignant complex cystic and solid breast lesions [7]. Comparing with solid breast lesions (OR: 17.02–31.6) [31, 32], nevertheless, irregular margin showed weaker correlation with malignancy prediction in complex cystic and solid lesions. The reason might be ascribed to the tension came from cystic portion.

Predominately cystic (≥50%) showed an OR value of 0.178 to malignancy prediction in complex cystic and solid lesions, the reasons are various. According to previous studies, the cystic portion might be mucin-like or hemorrhage-like, which are commonly caused by duct dilatation, acini, inflammation, tumor necrosis, or tumor hemorrhage [33]. The cystic portion might be inversely reflected to the disease progress, e.g. malignant progress from intraductal papilloma to intraductal papillary carcinoma, as well as the consolidated progress in inflamed lesions. The longer suffered from the disease, the less cystic portion was remained. In the present study, adenosis (n = 11) and intraductal papilloma (n = 9) were frequently to be found in the set of predominately cystic lesions (n = 30). With respect to those accompanied with thick wall or multiple septations (≥0.5 mm), such as honeycomb cysts, inflammation was the major reason (n = 3). For the predominately solid lesions, tumor necrosis and cystic degeneration were the major source of fluid component (43/63, 68.3%) [8].

In the present study, invalid SWS measurement (i.e.X.XX m/s) was found in 35 lesions. Dramatically, more than a half of the unmeasurable cases were found to be ductal in origin (19/35, 54.3% , p < 0.05), and invasive carcinoma accounted for overwhelming majority (14/19, 73.7% , p < 0.05). According to a recent study [34], the rates of unmeasurable SWS value (i.e. “X.XX m/s”) in normal breast tissue, benign lesion and malignant lesion were reported to be 1% , 17% and 76% , respectively. Analogously, unmeasurable SWS value occurred in 25.8% (16/62) of benign lesion and 61.3% (19/31) of malignant lesion (p < 0.05) respectively in our study. Additionally, Tada, et al. reported unmeasurable SWS value occurred in 81% of invasive cancer and 39% of DCIS [34]. And the rates were 73.7% (14/19) and 5.3% (1/19, p < 0.05) respectively in the current study. Based upon the results, it was indicated that the tissue with “X.XX m/s” observed in point SWS measurement should be highly suspected for malignancy. Furthermore, Berg, et al. and Vinnicombe, et al. have advocated that small (≤10 mm) and low grade invasive breast cancers were more likely to be soft, and DCIS were more frequently found to be soft than invasive cancers (>40%) [24, 35].

In agreement with a meta-analysis from Sadigh, et al. [20], the specificity of SE was higher while sensitivity was lower than conventional US in the current study. The diagnostic power of SE applied in complex cystic and solid lesions are not as strong as that applied in solid lesions. The answer could be pursued in a study from Booi, et al. [8], who stated that the decorrelating nature such as artifacts, fluid debris, noise, and some particulate matter inside of cysts could move randomly and cannot be tracked well by SE with being compressed. In solid lesions, point SWS measurement realized by VTQ/ARFI technique could not only overcome the limitations that SE have suffered from in terms of operator-dependence and reproducibility, but also quantitatively assess the tissue stiffness [25]. According to a meta-analysis from Li, et al. [36], point SWS measurement seems to be useful in breast malignancy prediction except for mucinous and DCIS, however, ARFI imaging was considered to be more reliable and repeatable than point SWS measurement. Without any prior study in malignancy prediction for complex cystic and solid lesions by using point SWS measurement to our best knowledge, it’s perplexing to find that the SWS value is even higher in benign lesions than malignancy in the present study. The perplexing result is also inconsistent with that realized by SWS imaging (Supersonic Imagine, expressed in kPa) in complex cystic and solid lesions previously [37]. To date, the theoretical cornerstone of shear wave imaging was structured upon a basic principle that the tissue in most malignancy was stiffer than that in benign lesions, and SWS value was observed to be higher in stiffer tissue [19]. The results occurred in our study might be explained as follows. First, the cystic degeneration and local glassy degeneration in the lesion could make it to be heterogeneous in stiffness. Thus, the disordered results could be ascribed to the fact that the tissue stiffness was entirely reflected by strain imaging while randomly and locally reflected by point SWS measurement. In addition, the early stage in disease progress has also contributed to the results. When staying in early stage, the stiffness change of the malignancy might have not yet beentriggered. The most possible reason, however, might be that unmeasurable results with “X.XX m/s” were not included in the analysis. In previous studies, the results with “X.XX m/s” sometimes were replaced by 8.4 m/s and the presence of “X.XX m/s” always indicates a hard lesion. Exclusion of “X.XX m/s” might lead to a lower SWS value in malignant lesions since “X.XX m/s” is mostly found in malignant lesions. Therefore, the true stiffness of malignant cystic and solid lesions might be different from the results of the current study, which should be further evaluated with a new generation of two-dimensional SWS imaging since invalid SWS measurement could be avoided using two-dimensional SWS imaging.

There were several limitations in the current study. First, bias of case selection may be occurred in the retrospective study. Cysts without solid portion, such as simple cyst, clustered micro-cysts and complicated cysts, were dismissed as low malignancy risky stratification (0–2%), while cysts containing viscous fluid that may give signals [22]. Secondly, CNB (sensitivity 88% , specificity 90% , PPV for malignancy 99% suspicious 100% , atypia 80%) [38] referred in our study was reported to have a wide range of false-negative rates when being used alone (2–38%) [39]. Moreover, a range of 17–27% in DCIS confirmed in CNB was upgraded to invasive carcinoma in the excision [40]. Therefore, the reference standard defined as a combination of pathology and long-term follow-up is strongly recommended in the future study. Third, due to the double-screen display, reader could be subjectively influenced by lesion features displayed on grey-scale screen when assessing SE or ARFI imaging. Additionally, SE and ARFI techniques were various across different manufacturers which made the generalizability of our results unclear. As was theoretically based, the faster the data acquired, the fewer influence came from breath and heartbeats. Finally, investigations of elastographical diagnoses in our study were based on a small number of samples. Enlarged samples for further study areneeded.

5 Conclusions

In conclusion, US BI-RADS category, strain elastography score, ARFI imaging patterns and point SWS measurement are useful for malignancy prediction of complex cystic and solid breast lesions. The result that SWS for malignant lesions is lower than benign one should be carefully interpreted since invalid SWS measurement is excluded for analysis. The true stiffness of malignant cystic and solid lesions should be further evaluated with a new generation of two-dimensional SWS imaging.

Conflict of interest

All the authors certify that there is no actual or potential conflict of interests in this article.

Footnotes

Acknowledgments

This work was supported in part by Grant SHDC12014229 from Shanghai Hospital Development Center, Grants 14441900900 and 16411971100 from Science and Technology Commission of Shanghai Municipality.

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