Evaluation of plasma cell mastitis with superb microvascular imaging

Abstract

BACKGROUND:

Plasma cell mastitis (PCM), a common type of mastitis often mimics malignancy clinically and radiologically.

OBJECTIVE:

The study was designed to explore the diagnostic value of superb microvascular imaging (SMI) in differentiating PCM from malignant breast lesions.

METHODS:

A total of 95 breast lesions underwent conventional ultrasound (US) and SMI examination between May 2016 and April 2018. Vessels were detected in SMI in a quantitative manner. Blood flow parameters including systolic peak velocity (SPV), resistance index (RI), and pulsatility index (PI) were evaluated. We further assessed the diagnostic performances of US and US+SMI.

RESULTS:

The majority of PCM were in regular shape and displayed no calcification compared with malignant breast lesions. Regarding blood flow parameters, PCM obtained significantly lower mean value of RI and PI compared with malignant lesions (P < 0.05). The sensitivity, specificity and accuracy rate of US+SMI (84.62%, 76.47%, 83.16%) was significantly higher than those of US (78.21%, 64.71%, 75.59%).

CONCLUSIONS:

The present study supports that SMI is a novel ultrasound technology in revealing micro-vessels in breast lesions. The combined modality of US+SMI presented a better diagnostic performance in making a distinction between PCM and malignant breast carcinomas.

1 Introduction

Mastitis is a common type of benign breast lesion with a diverse array of clinical presentations. One variant with plenty of plasma cells has been termed plasma cell mastitis (PCM). It is often known as the most common encountered inflammation of the nonlactating breast [1]. Inflammation is mostly accompanied by angiogenesis. Plenty of researches have documented the role of inflammation in promoting development of new vasculatures [2]. In turn, angiogenesis is considered as an essential event in oncology. It is pivotal in local growth, invasion, and distant metastasis of cancer [3]. Therefore, careful clinical examination is the cornerstone of diagnosis for breast infection since it frequently represents a diagnostic challenge on differentiating PCM from breast carcinoma of lobular infiltrating type [4]. Ultrasound is a useful modality as an adjunct to both physical examination and mammography for screening and differentiating benign and malignant breast masses. An emerging form of Doppler ultrasonography called superb microvascular imaging (SMI) has been applied to determine microvascular blood flow. SMI suppresses clutter to delineate wider range of blood flow signals with higher resolution. Consequently, it is capable of detecting both low-velocity and high-velocity flows.

Given the paucity of researches in identifying the diagnostic performance of SMI in PCM, the current study was designed to explore the clinical use of SMI for distinguishing PCM from malignant breast carcinomas.

2 Materials and methods

2.1 Ethics committee

The prospective study was approved by our Ethics Committee. All enrolled patients were notified of the examinations and procedures and all patients provided informed consent.

2.2 Patient selection

From May 2016 to April 2018, 247 patients underwent conventional ultrasound (US) detected with breast lesions in our hospital. For the purpose of distinction between PCM and breast carcinoma, benign lesions other than PCM were therefore excluded from the present study. All patients received conventional US and SMI prior to US-guided core needle biopsy or surgery. Images were complete, and each breast lesion obtained histologic confirmation. For patients with multiple lesions, the most suspicious lesion was selected. Eventually, 95 patients (age range: 22–73 years) with 95 lesions were recruited into this study. The flowchart in (Fig. 1) presented the selection process.

Fig.1

Flowchart for patient selection.

2.3 Conventional US, SMI measurement and imaging interpretation

All patients first underwent gray-scale US examination in supine position with the arms elevated. The descriptive ultrasonic features were recorded in our study: lesion size in diameter, margin, shape, echo pattern, posterior acoustic features and types of calcification. The targeted lesion was further rated by using the latest US BI-RADS of the American College of Radiology (ACR) [5]. Thereafter, SMI measurement was performed. The velocity scope of SMI was adapted to 1.0 to 2.0 centimeters per second. Little pressure was applied through the transducer to prevent from the risk of vessel collapse. Consequently, the evaluation of vascularity in and around the lesions was performed. Systolic peak velocity (SPV), resistance index (RI), and pulsatility index (PI) for each lesion were recorded.

Both conventional US and SMI were conducted using a TOSHIBA Aplio 500 (Toshiba Medical System Corporation, Tokyo, Japan) with high-frequency line array transducers. The frame rate was 14 MHz for conventional US and >50 MHz for SMI examination, respectively. The same radiologist (Y-C. Z) conducted the entire examinations. This radiologist had more than 5 years of experience in breast imaging and had 6 months of experience in SMI measurement. He recorded all the images on our internal online database. The images were thereafter evaluated by 2 radiologists with consensus (Y.Z, and S-H. D), who were with 10 and 5 years of experience in breast imaging and 12 months of experience in SMI. Once any disagreement occurred, they would consult the senior expert (Q.J) who obtained more than 15 years of experience in breast ultrasonography and 18 months of experience in SMI. All three interpreters were blind to the pathological findings.

The interpreters applied a 3-step reading process. First, they evaluated the risk of malignancy on the foundation of basic sonographic features according to BI-RADS. Secondly, they rated blood flow signals based on Adler’s classification [6]. Vascularity was categorized from Grade 0 to Grade 3, depending on the amount of vasculature. Grade 0 is regarded as absent. Minimal (Grade 1) flow is generally regarded as 1 or 2 pixels containing flow (<0.1 cm in diameter). When a certain number of small vessels and/or a main vessel was seen, clinicians graded it as moderate (Grade 2). Marked (Grade 3) vascularity was rated when 4 or more vessels were visualized. In the end, they corrected the risk of malignancy of each breast lesion adding the outcomes from SMI examinations.

2.4 Statistical analysis

All data were analyzed by STATA software package (Version 15.0; StataCorp, Texas, USA). The mean values of quantitative datum were expressed as mean±standard deviation (SD) on the condition of normal distribution. Chi-squared test or Fisher’s exact test was applied in categorical variables, while independent t test was applied in comparison of continuous variables. The potential associated factors for identifying PCM and malignancy on US and SMI were investigated using univariate and multivariate logistic regression analyses. We further formulated a receiver operating characteristic (ROC) curve to observe the optimum threshold value of US and US+SMI. Sensitivity, specificity, and correct rate were calculated based on the cut-off value. Areas under the ROC (AUCs) of different diagnostic modalities were compared using the chi-squared test. The statistical analysis was done with pathological results as the criterion standard. The statistical significance level was defined as 0.05.

3 Results

3.1 Lesion diagnostic results

Of all 95 breast lesions, 17 (17.89%) lesions were pathologically confirmed as PCM. The remaining 78 malignant lesions were further categorized as invasive ductal carcinomas (n = 59), ductal carcinoma in situ (DCIS) (n = 12), solid papillary carcinomas (n = 3), intraductal papillary carcinomas (n = 3), and an invasive micropapillary carcinoma (n = 1). Table 1 presents the classic ultrasonic features in terms of PCM and malignant lesions. 82.4% of PCM displayed wider than tall while 80.8% of the malignant lesions showed taller than wide (P < 0.001) in contrast. The majority of PCM (94.1%) presented no calcification while less than half of the malignant lesions (41.0%) were with the same character (P = 0.011).

Table 1
Basic characteristics and ultrasonic features of the patients

PCM Malignancy Total P value

Age 41.59±7.48 56.73±8.53 54.02±10.16 <0.001^*

Size 23.13±12.81 28.08±9.31 27.20±10.13 0.073

Margin 0.942

Circumscribed 4 (23.5%) 19 (24.4%) 23 (24.2%)

Not circumscribed 13 (76.5%) 59 (75.6%) 72 (75.8%)

Echo pattern 0.053

Hyperechoic 0 (0.0%) 5 (6.4%) 5 (5.3%)

Isoechoic 1 (5.9%) 14 (17.9%) 15 (15.8%)

Hypoechoic 12 (70.6%) 50 (64.1%) 62 (65.3%)

Complex 4 (23.5%) 9 (11.5%) 13 (13.7%)

Posterior acoustic feature 0.335

Shadowing 13 (76.5%) 53 (67.9%) 66 (69.5%)

No posterior acoustic feature 3 (17.6%) 12 (15.4%) 15 (15.8%)

Enhancement 1 (5.9%) 13 (16.7%) 14 (14.7%)

Shape <0.001^*

Wider than tall 14 (82.4%) 15 (19.2%) 29 (30.5%)

Taller than wide 3 (17.6%) 63 (80.8%) 66 (69.5%)

Calcification 0.011*

No calcification 16 (94.1%) 32 (41.0%) 48 (50.5%)

Macrocalcification 1 (5.9%) 3 (3.8%) 4 (4.2%)

Microcalcification 0 (0.0%) 36 (46.2%) 36 (37.9%)

Mixed calcification 0 (0.0%) 7 (9.0%) 7 (7.4%)

	PCM	Malignancy	Total	P value
Age	41.59±7.48	56.73±8.53	54.02±10.16	<0.001^*
Size	23.13±12.81	28.08±9.31	27.20±10.13	0.073
Margin				0.942
Circumscribed	4 (23.5%)	19 (24.4%)	23 (24.2%)
Not circumscribed	13 (76.5%)	59 (75.6%)	72 (75.8%)
Echo pattern				0.053
Hyperechoic	0 (0.0%)	5 (6.4%)	5 (5.3%)
Isoechoic	1 (5.9%)	14 (17.9%)	15 (15.8%)
Hypoechoic	12 (70.6%)	50 (64.1%)	62 (65.3%)
Complex	4 (23.5%)	9 (11.5%)	13 (13.7%)
Posterior acoustic feature				0.335
Shadowing	13 (76.5%)	53 (67.9%)	66 (69.5%)
No posterior acoustic feature	3 (17.6%)	12 (15.4%)	15 (15.8%)
Enhancement	1 (5.9%)	13 (16.7%)	14 (14.7%)
Shape				<0.001^*
Wider than tall	14 (82.4%)	15 (19.2%)	29 (30.5%)
Taller than wide	3 (17.6%)	63 (80.8%)	66 (69.5%)
Calcification				0.011*
No calcification	16 (94.1%)	32 (41.0%)	48 (50.5%)
Macrocalcification	1 (5.9%)	3 (3.8%)	4 (4.2%)
Microcalcification	0 (0.0%)	36 (46.2%)	36 (37.9%)
Mixed calcification	0 (0.0%)	7 (9.0%)	7 (7.4%)

PCM Plasma cell mastitis. ^*Indicates statistically significant difference.

3.2 Vascularity findings

The amounts of vascularity were examined on the foundation of Adler’s classification as shown in (Table 2). SMI exhibited noticeable variance between malignant masses and PCM (P = 0.019). Most of the PCM (41.18%) presented a certain number of small vessels while 46.15% of the malignant lesions had enriched blood flow signals. Furthermore, SPV, RI and PI all presented significant difference between PCM and malignant lesions (P = 0.041, P < 0.001, P = 0.002). The mean SPV of malignancy (21.51±13.02 cm/s) was significantly higher than that of PCM (14.70±3.80 cm/s). Both the mean value RI and PI of PCM (0.60±0.08, 1.20±0.21, respectively) was significantly lower than those of malignant lesions (0.80±0.11, 1.96±0.85, respectively).

Table 2
Vascularity findings

PCM Malignancy z P value

Adler’s classification

Grade 0 5 (29.41%) 11 (14.10%)

Grade 1 3 (17.65%) 9 (11.54%) 2.34 0.019^*

Grade 2 7 (41.18%) 22 (28.21%)

Grade 3 2 (11.76%) 36 (46.15%)

SPV 14.70±3.80 21.51±13.02 2.05 0.041^*

RI 0.60±0.08 0.80±0.11 4.28 <0.001^*

PI 1.20±0.21 1.96±0.85 3.14 0.002^*

	PCM	Malignancy	z	P value
Adler’s classification
Grade 0	5 (29.41%)	11 (14.10%)
Grade 1	3 (17.65%)	9 (11.54%)	2.34	0.019^*
Grade 2	7 (41.18%)	22 (28.21%)
Grade 3	2 (11.76%)	36 (46.15%)
SPV	14.70±3.80	21.51±13.02	2.05	0.041^*
RI	0.60±0.08	0.80±0.11	4.28	<0.001^*
PI	1.20±0.21	1.96±0.85	3.14	0.002^*

PCM Plasma cell mastitis. SPV = mean systolic peak velocity (mean±SD); RI = mean value of resistance index (mean±SD); PI = mean value of pulsatility index (mean±SD). ^*Indicates statistically significant difference.

3.3 Univariate and multivariate logistic analyses

Univariate logistic analysis presented that the following US characteristics shown significant correlation with PCM: regular shape (OR = 19.6, P < 0.001), no calcification (OR = 23.0, P = 0.003), RI ≤0.68 (OR = 51.0, P < 0.001), PI ≤1.41 (OR = 17.9, P < 0.001), and rated as Grade 2 or lower according to Adler’s classification (OR = 1.9, P = 0.018) (Table 3). In multivariate logistic analysis, RI ≤0.68 (OR = 83.0, P < 0.001) was the strongest predictor for PCM, followed by PI ≤1.41 (OR = 28.9, P = 0.008), and no calcification (OR = 39.2, P = 0.013) (Table 4).

Table 3
Univariate logistic regression analysis for ultrasonic features of PCM

Predictive factors OR (95% CI) P value

Regular shape (wider than tall) 19.6 (4.99–76.99) <0.001^*

No calcification 23.0 (2.90–182.28) 0.003^*

RI ≤0.68 51.0 (10.11–257.16) <0.001^*

PI ≤1.41 17.93(3.793–84.804) <0.001^*

Adler≤ Grade 2 1.861(0.3196–3.401855) 0.018^*

Predictive factors	OR (95% CI)	P value
Regular shape (wider than tall)	19.6 (4.99–76.99)	<0.001^*
No calcification	23.0 (2.90–182.28)	0.003^*
RI ≤0.68	51.0 (10.11–257.16)	<0.001^*
PI ≤1.41	17.93(3.793–84.804)	<0.001^*
Adler≤ Grade 2	1.861(0.3196–3.401855)	0.018^*

Table 4

Multivariate logistic regression analysis for PCM

Independent factors	OR (95% CI)	P value
No calcification	39.21867 (2.18552–703.7703)	0.013^*
RI ≤0.68	82.99202 (7.562251–910.797)	<0.001^*
PI ≤1.41	28.8516 (2.4303–342.5076)	0.008^*

3.4 BI-RADS correction and diagnostic performance of different modalities

In total, 7 breast lesions were downgraded to a lower level while 13 breast lesions were upgraded to a higher level (Table 5). Both downgrading and upgrading were found in PCM and malignant lesions. To be more precisely, downgrading occurred in 3 PCM from 4a to 3, and 2 PCM from 4b to 4a, 2 malignancies from 5 to 4c, while upgrading occurred in 1 PCM and 2 malignancies from 3 to 4a, and the remaining 10 malignant neoplasms were all adjusted to a higher level. Thus, the sensitivity, specificity and accuracy rate of US+SMI (84.62%, 76.47%, 83.16%) was significantly higher than those of US (78.21%, 64.71%, 75.59%) (Table 6). The AUC values of US+SMI and US were 0.779 (95% CI: 0.6858–0.8730) and 0.8801 (95% CI: 0.8073–0.9529), respectively (P < 0.001) (Fig. 2).

Fig.2

ROCs for 3 diagnostic modalities.

Table 5

The correction of BI-RADS category in 95 breast masses

Pathological diagnosis	No. of masses	Before the correction of BI-RADS category (US)
		3	4a	4b	4c	5
PCM	17	4	7	6	0	0
Malignancy	78	8	9	29	18	14
Pathological diagnosis	No. of masses	Final BI-RADS category (US+SMI)
		3	4a	4b	4c	5
PCM	17	6	7	4	0	0
Malignancy	78	6	6	32	19	15
The correction of BI-RADS category by different technique
Different technique	BI-RADS category
		3	4a	4b	4c	5
US		12	16	35	18	14
US+SMI		12	13	36	19	15

Table 6

Diagnostic performances of different modalities

	Cut-off	Sensitivity	Specificity	Accuracy rate	AUC	95% CI	P
US	4a	78.21%	64.71%	75.59%	0.779	0.6858–0.8730	<0.001
US+SMI	4a	84.62%	76.47%	83.16%	0.8801	0.8073–0.9529	<0.001

AUC area under the receiver operating characteristic curve; CI confidence interval; US ultrasonography; SMI superb microvascular imaging.

4 Discussion

PCM was firstly known as mastitis obliterans in 1909 [7]. It was not until 1931 that Ewing proposed the term of plasma cell mastitis for discovering chiefly of plasma cells exudate [8]. Clinically, PCM was highly associated with localized pain with swelling and often presents with nipple retraction and sub-areolar breast lesions. Furthermore, PCM often occurs in an ipsilateral or contralateral manner. In our study, the majority of patients presented inflammation surrounding the nipple and areola. Varying degrees of nipple retraction were also found in most of the patients. Even though PCM is a rare benign breast disease without demonstrated correlation with breast carcinoma risk, it has been frequently confused with malignancy. Distinguishing PCM from breast carcinoma with routine imaging methods such as conventional US and mammography is challenging [4]. Therefore, it is in need of innovative imaging technology. SMI emerges as a pioneering vascular imaging technique with new adaptive algorithm to delineate both high and low velocity blood flows with higher resolution and fewer motion artifacts, whereas color Doppler imaging uses a wall filter to remove clutter and motion artifacts that leads to the loss of low-velocity signals. Motion-induced artifacts increase when pulse repetition frequency decreases substantially. SMI displays lower pulse repetition frequencies (220–234 Hz) than power Doppler imaging (870–966 Hz). Therefore, SMI is superior to revealing low-velocity blood flows with fewer motion artifacts compared with conventional Doppler imaging. The capability of divulging subtle bloodstreams has been widely proved in various studies, not limited in the evaluation of breast mass vasculatures [9 –12]. In this work, we explored the diagnostic value of SMI in differentiating PCM from malignant breast neoplasms.

In our study, PCM shared some similarities regarding ultrasonic features with malignant breast lesions such as ill-defined margins and hypoechoic structure. Those features might make it difficult to differentiate PCM from breast carcinoma (Fig. 3). However, vast majority of PCM were wider than tall and displayed no calcification compared with malignant breast lesions (Fig. 4).

Fig.3

Evaluation of blood build-up in a lesion of the left breast with SMI in a 63-year-old female. According to Adler’s classification, microvascular imaging was rated as Grade 2 with SMI. The lesion was classified as US BI-RADS category 4c and pathologically proved as invasive ductal carcinoma.

Fig.4

Evaluation of blood build-up in a lesion of the right breast with SMI in a 59-year-old female. According to Adler’s classification, microvascular imaging was rated as Grade 3 with SMI. The lesion was classified as US BI-RADS category 3 and pathologically proved as PCM.

Doppler ultrasonography has been widely applied to detect distinctions in bloodstream of healthy organs and cancerous tissues [13 –15]. Previous researches indicated that increased RI correlated with breast carcinoma [16, 17]. Youssefzadeh et al. [18] evaluated RI of 56 breast lesions and demonstrated that the mean RI of malignant lesions was 0.7±0.08 with a range of 0.56 to 0.9 while that of benign ones was a little bit lower (0.62±0.08). Davoudi et al. [19] came to a similar finding after examining 38 breast lesions that an RI over 0.7 might suggest malignancy. SMI is an advanced Doppler technique that improves the visualization of blood streams [9, 20]. However, by far few studies applied SMI in examining blood flow indexes such as RI and PI. In the present study, we applied SMI in evaluating 95 breast lesions including 17 of them as PCM and found that PCM obtained lower mean RI (0.60±0.08) than the malignant lesions (0.80±0.11). Our finding was consistent with the previous findings. Sirous et al. [21] conducted power Doppler imaging analysis of 1110 breast lesions and figured out that PI was significantly higher in malignant breast neoplasms (1.49±0.51) in comparison to that in benign ones (1.13±0.38) (p = 0.001). Del Cura et al. [22] analyzed 826 breast lesions regarding lesion vascularity, PI and RI in power and duplex Doppler ultrasound images, and came to the consistent finding that both RI and PI values were significantly higher in malignancy (p < 0.001). In the present study, we applied an advanced Doppler US technique to evaluate the same parameters and came to the similar finding that both mean value of RI (0.60±0.08) and PI (1.20±0.21) of PCM was significantly lower than those of malignant lesions (0.80±0.11, 1.96±0.85, respectively). Carcinoma growth might lead to an increase of tissue pressure and eventually resulted in the reduction of distal flow. In other words, tumors presented with reduced diastolic flows [18]. Therefore, the mean value of RI of patients with PCM was significantly lower than that in those with malignant lesions (P < 0.001).

Zhao et al. [23] evaluated vascularity in 135 breast lesions and found that SMI was superior to displaying more flow signals and details of micro-vessels. The prevalence of malignancy was higher (64.7%, 33/51) in hyper-vascular lesions, while only 19.5% of avascular and hypo-vascular malignant lesions were reported. In the present study, we came to the similar finding that 36 out of 78 malignant lesions were hyper-vascular while 2 out of 17 PCM were with the same feature. The majority of PCM were reported as avascular (29.41%) and hypo-vascular (58.82%). That was to say intra-nodular vascularity was significantly correlated with breast malignancy. However, in multivariate logistic analysis, rich internal flow was not an independent risk factor to differentiate PCM from malignancy. Instead, RI ≤0.68 (OR = 83.0, P < 0.001) was the strongest predictor.

The superposition of values that provided by blood flow parameters such as RI, PI and SPV was undeniable [18, 24], however, themselves alone did not allow the perfect accurate distinguishing between benign and malignant breast lesions [25, 26]. These parameters were valuable when analyzed together with other ultrasonic features. Therefore, in the present study, we applied a combined modality of US+SMI in distinguishing malignant breast lesions from PCM, adding BI-RADS classification. 6 out of 17 PCM were misdiagnosed as malignant breast carcinoma in US examination. Taking parameters detected by SMI into consideration, 2 PCM were downgraded from 4b to 4a. In other words, the specificity increased from 64.71% (11/17) to 76.47% (13/17). The reason for downgrading was less vasculature were revealed from PCM and lower RI (0.63, 0.59, respectively) and PI (1.21, 1.18, respectively) were reported. With the combination of 2 methods, the proposed combination of SMI and US reached a higher sensitivity (84.62%), specificity (76.47%) and accuracy rate (83.16%) in making a distinction between malignant breast lesions and PCM. That could lead to a reduction in the number of unnecessary surgical procedures performed in patients with PCM.

In this study, there were 78 malignant and 17 PCM. Further study with a larger sample size is suggested. Besides of the sample size, our study has other limitations. Secondly, all the examinations were conducted by the same radiologist, so the interpretation of inter-observer differences was missed.

PCM is an infrequently encountered disease that can mimic breast carcinoma. However, the majority of PCM in the present study displayed wider than tall shape and without calcification compared with malignant breast lesions. The present study supports that SMI is a novel and promising ultrasound technology in revealing micro-vessels in breast lesions. Regarding vascularity features, PCM obtained lower mean values of RI and PI in comparison to malignancy. The combined modality of US+SMI presented a better diagnostic performance in differentiating malignant breast lesion from PCM.

Footnotes

Acknowledgments

This work was supported by the Pu Dong New Area Health and Family Planning Commission Important Vulnerable Course Project (no. PWzbr 2017-10).

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