Added value of strain elastography in the characterisation of breast lesions: A prospective study

Abstract

Background

Elastography is a new promising ultrasonographic technique which is used to differentiate benign and malignant breast lesions based on the stiffness of the lesion.

Purpose

To determine the role of strain elastography in characterisation of breast lesions and to compare the diagnostic performances of strain elastography and conventional ultrasound (US).

Methods

In total, 113 breast lesions in 100 women were prospectively evaluated by US and strain elastography followed by the histopathological examination. Elastography score based on the Tsukuba colour scale and strain ratio were determined for each lesion. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were calculated for each modality and the diagnostic performances were compared. The best cut-off point was calculated for each of the elastography parameters using the receiver operator curve analysis.

Results

Out of the 113 lesions, 40 were malignant (35.4%) and 73 were benign (64.6%). The area under the curve for elastography score showed significant difference with that of US: 0.98 versus 0.90 (Difference = 0.08, p =0.02). The elastography parameters were more specific as compared to US (ES-95 and SR-93% vs. 63%, p < 0.05) with a high negative predictive value. The combined use of elastography and US gave better results with 95% sensitivity, 94% specificity, 94% accuracy and negative predictive value reaching 97%.

Conclusion

Strain elastography is a useful adjunct to conventional ultrasonography. The combined use of strain elastography and ultrasound improves the characterisation of breast lesions and helps in down-staging of assigned BI-RADS category, thereby avoiding unnecessary biopsies. ES is the most useful elastography parameter to differentiate between benign and malignant breast lesions.

Introduction

With approximately two million new cases in 2018, breast cancer is the most commonly diagnosed cancer among women globally.¹ It is also the leading cause of cancer death among women worldwide with an estimated 626,679 deaths in 2018.¹ Breast cancer is the most common cancer among Indian females with an age-adjusted rate of 25.8 per 100,000 women, and high mortality estimated at about 12.7 per 100,000 women.² Early detection is the key for successful management of breast cancer. Various screening programs incorporating mammography and ultrasonography are being run worldwide for the detection of breast cancer. These are under continuous evolution with ongoing research. Presently, biopsy with histopathological examination is the gold standard investigation for the definitive diagnosis of breast lesions. Apart from breast cancer, a large number of benign lesions are commonly encountered in clinical practice.

Conventional B-mode ultrasonography (US) is the most widely used modality for the evaluation of breast lesions. Using the standard American College of Radiology (ACR) Breast Imaging-Reporting and Data System (BI-RADS) lexicon, the lesions are placed in different categories, based on which clinical actions are taken. Most of the lesions categorized into BI-RADS 3 or 4 A pose a diagnostic dilemma for the treating clinician and the reporting radiologist. They are low suspicion lesions with a reported incidence of malignancy as <10%. About 98% of the lesions graded as BI-RADS 3 are histologically benign, and therefore the current guidelines suggest the short-term follow-up. Nevertheless, about 2% of these lesions eventually turn out to be malignant, which are missed at initial diagnosis. Compliance with regular follow-up for BI-RADS 3 lesions is poor due to ignorance and cost factors, thereby prompting clinicians for biopsy over regular follow-ups, which in most of the cases turn out to be negative.

BI-RADS 4 lesions have a low to moderate probability of malignancy (2–94%) and biopsy is recommended. Among BI-RADS category 4 A lesions, approximately only 2–9% turn out to be histologically malignant, and a much larger proportion of patients undergo invasive diagnostic procedures that could be avoided if a better noninvasive imaging technique was available for accurate diagnosis.

Ophir et al.³ in 1991 introduced the concept of ultrasound elastography. Elastography is a noninvasive technique which uses the mechanical property of tissue elasticity on external compression to assess the stiffness of tissues analogous to clinical palpation. By offering additional information about tissue stiffness, real-time tissue elastography can help in differentiation between benign and malignant disease, and thus improving the accuracy of diagnosis of breast cancer.⁴ Elastography was first introduced into clinical practice in 2009 for the characterization of breast lesions. Later, its application extended to multiple organs including thyroid, prostate, liver, and musculoskeletal tissues.

Currently, two types of elastography technique are used in clinical ultrasound systems; strain and shear wave. Each technique has its own advantages and disadvantages.

Recently, ultrasound elastography has been incorporated into the 5th edition of the ACR BI-RADS lexicon.⁵ Bojanic et al.⁶ concluded that strain elastography can be used to upgrade or downgrade the BI-RADS category of breast lesions.

A prospective study was designed in our institute to evaluate the diagnostic performance and the accuracy of strain elastography for the characterization of breast lesions as compared to conventional ultrasonography. Additionally, we aimed to determine whether elastography could downgrade or upgrade BI-RADS 3 and 4 lesions, thereby recoursing biopsies only to suspicious stiff lesions.

Methods

The study was conducted in compliance with the Declaration of Helsinki principle and was approved by our institutional review board. Written informed consent was obtained from all the participants before being included in the study. A total of 113 lesions in 100 patients referred for breast ultrasound were analysed from August 2018 to June 2019 at the Department of Radio-diagnosis in our hospital.

Real-time ultrasound followed by strain elastography (SE) was performed using a 3–12 MHz linear array transducer on a Samsung RS80A unit (Samsung Medison BLDG., 42 Teheran-ro 108-gil, Gangnam-gu, Seoul 135-851, South Korea) by one of two radiologists with 8 and 10 years of experience in breast ultrasound. The two radiologists involved in this study received training in elastography for a period of 12 months by the Samsung applications specialist. The images were later reviewed together and the final diagnosis was made by consensus.

Patient selection

Inclusion criteria

Females in the age range of 16–80 years with sonographically visible solid breast lesions, measuring less than 3 cm, classified as BI-RADS 3, 4 and 5 on conventional ultrasound were included in the study. Among BI-RADS 3 lesions, only those lesions which were subjected to fine needle aspiration cytology or biopsy (on clinician’s or patient’s request) were included in the study.

Exclusion criteria

Cystic lesions, solid lesions classified as BI-RADS category 2, lesions measuring larger than 3 cm in diameter, lesions located near the skin surface or the chest wall and lesions without cytologic/histopathologic diagnosis were excluded from the study.

Conventional sonography

The lesions were first assessed by conventional B-mode ultrasonography using a radial scanning pattern with patients lying in a supine position. Each lesion was assigned a BI-RADS category using conventional ultrasound features like shape, echotexture, margin, orientation and posterior acoustic characteristics.

Elastography technique and parameters

Next, SE was performed. Data were acquired by setting the field-of-view box including the region from the subcutaneous fat layer to the pectoralis muscle layer, avoiding the rib cage. Due care was taken to include the entire lesion within the field of view. The target lesion was vertically compressed with the application of optimum light external pressure to the transducer (an adequate probe pressure on the target lesion was displayed as two or three blocks of green in the vertical column on the left side of the monitor of the ultrasound scanner; a partially adequate pressure was displayed as single or no block of colour and high levels of pressure displaying as four to five blocks).

The ES was determined on a 5-point Tsukuba classification proposed by Itoh et al.⁷ According to Tsukuba classification, a score of 1 is given when the entire lesion is evenly shaded in green, indicating that the whole lesion is soft with homogeneous strain throughout (Figure 1). A score of 2 is represented by a mixed pattern of green and blue suggesting that the greater part of the lesion is soft with a few interspersed areas of stiffness (Figure 2). A score of 3 is given when the lesion shows strain at the periphery represented by green shade, with central stiffness represented in blue (Figure 3). A score of 4 is given when the lesion shows homogeneous shading in blue indicating that the entire lesion is stiff (Figure 4). Finally, a score of 5 is given when the entire lesion and surrounding area show blue shading indicating stiffness in and around the lesion (Figure 5). Lesions with ES 1 to 3 were considered benign, and the lesions with ES 4 and 5 were suspected to be malignant.

Figure 1.

A case of fat necrosis showing strain in entire lesion as represented by even shading of the lesion in colour green on elastography suggesting score 1.

Figure 2.

A case of fibroadenoma showing strain in most of the lesion represented by green colour with part of the lesion showing no strain, shaded in blue with a score of 2.

Figure 3.

A case of fibroadenoma showing mosaic pattern of green and blue colour suggesting a score of 3.

Figure 4.

A case of infiltrating carcinoma showing stiffness in the entire lesion represented by even shading with blue colour suggesting a score of 4.

Figure 5.

A case of invasive ductal carcinoma showing stiffness in entire lesion as well as in surrounding tissue represented by shading of lesion and surrounding tissue in blue colour suggesting a score of 5.

Strain ratio was calculated by placing first the region of interest (ROI) in the target lesion and second ROI in lateral subcutaneous fat tissue of similar size and at the same depth as the target lesion.

Histopathology

Finally, the lesions were subjected to either ultrasound-guided core biopsy or surgically excised. Histopathological results were used as the reference standard for the comparison of conventional ultrasound and elastography findings.

Statistical analysis

The sonographic and elastographic parameters for benign and malignant lesions were compared relative to the histopathological diagnosis by using the Mann–Whitney U test. The level of significance was set at a p value of 0.05. The receiver operating curve (ROC) analysis was used to determine the optimal threshold, area under the curve (AUC), specificity and sensitivity of the tested parameters. Statistically significant differences between the areas under the receiver operating curve were reported as 95% confidence intervals. ROC curves were compared by using the deLong test. Statistical analysis was performed using the statistical software R version 3.6.0 (R core team, 2019).

Results

We included 100 women with 113 breast lesions. There were 73 (64.6%) benign and 40 (35.4%) malignant lesions. The mean age for benign lesions was 39.9 years and 55.8 years for malignant lesions (age range 16–80) (Table 1). The malignant lesions showed higher ES and SR and a higher BI-RADS category as compared to benign lesions (p < 0.001) (Table 1). The median ES for benign lesions was 2 and for malignant lesions it was 5. The mean SR was 1.82 for benign and 4.67 for malignant lesions.

Table 1.

Mean values of variables with respect to histopathological diagnosis.

Variants	Mean	SD	Median	IQR	p value
Age
Benign	39.97	10.81	40	13.5	<0.001
Malignant	55.87	14.69	58	22.5
BIRADS
Benign	3.37	0.49	3	1	<0.001
Malignant	4.65	0.66	5	0.25
ES
Benign	2.42	0.62	2	1	<0.001
Malignant	4.67	0.62	5	0.25
SR
Benign	1.82	0.85	1.6	0.92	<0.001
Malignant	4.67	1.31	4.65	1.32

ROC analysis for ES showed the highest sensitivity (92.3%) and specificity (94.59%) at a cut-off value of 3 (Figure 6) with AUC being 0.98. The positive predictive value (PPV), negative predictive value (NPV) and accuracy were 90%, 95.8% and 93.8%, respectively. For strain ratio, the optimal cut-off value was 3.0, with a sensitivity of 89.7% and specificity of 93.2% with AUC 0.96 (Figure 7). We obtained PPV of 87.5%, NPV of 94.5% and accuracy of 92% at this cut-off. A cut off of 3.5 for SR showed lower sensitivity (87%) but higher specificity (95%). The sensitivity, specificity and accuracy for the conventional ultrasound alone were 90%, 63.8% and 73% respectively with AUC 0.90 (Figure 8). PPV was 58.7% and NPV was 92%. The overall sensitivity and specificity of strain elastography combining both ES and SR were 92% and 93%, respectively. The sensitivity, specificity and accuracy of conventional ultrasound and SE combined together were 95%, 94% and 94.69%, respectively. PPV was 90.48% and NPV was 97.18%.

Figure 6.

ROC curve for elasticity score or Tsukuba score, showing sensitivity of 92% and specificity of 95% at cut off value of >3.

Figure 7.

ROC for strain ratio showing sensitivity of 90% and specificity of 93% at cut off value of 3.

Figure 8.

ROC for conventional ultrasound showing sensitivity of 90% and specificity of 63% at cut off of 3 (BIRADS 3).

There was a statistically significant difference in the AUC for ES and conventional US (difference between areas = 0.08, 95% confidence interval [CI]: p = 0.011) (Figure 9). The AUC for ES and SR (difference between areas = 0.02, 95% CI: p = 0.17) and conventional US and SR (difference between areas = 0.06, 95% CI: p = 0.075) did not differ significantly (Figure 9).

Figure 9.

Combined ROC for ES, SR and US showing respective AUC. AUC showed significant difference between US and ES.

Out of 113 lesions, 32 lesions were classified as BI-RADS 4 by conventional ultrasound features. Among these, 6 were found to be malignant and 26 benign on histopathological examination. On the basis of elastography parameters, 22 (85%) lesions were correctly predicted as benign with overall sensitivity, specificity and diagnostic accuracy of elastography being 80%, 81.5% and 81%.

Of 51 lesions classified as BI-RADS 3 by conventional ultrasonography, 4 were found to be malignant and 47 benign on the histopathological examination. Among these, 82.35% were correctly predicted as benign and 50% lesions were correctly predicted as malignant based on the elastography parameters (ES and SR) with a sensitivity of 50%, specificity of 89.36% and diagnostic accuracy of 86.27%. The PPV for malignancy being 28.57% and NPV being 95.45%.

There were 30 BI-RADS category 5 lesions by conventional ultrasonographic features. Conventional ultrasound and elastography findings were equally sensitive and specific in this category.

The distribution of lesions according to histopathological findings is outlined in Table 2. The most common malignant lesion was invasive ductal carcinoma (80%) and the most common benign lesions were fibroadenomata (79.5%) followed by the benign fibroepithelial lesions (9.6%).

Table 2.

Histopathological differential diagnosis amongst malignant and benign lesions.

Malignant lesions		Benign lesions
Histopathological diagnosis	NumbersTotal=40	Histopathological diagnosis	NumbersTotal = 73
Invasive ductal carcinoma	27(67.5%)	Fibroadenoma	58(79.5%)
Invasive mucinous carcinoma	4(10%)	Benign fibroepithelial lesion	7(9.6%)
Invasive poorly differentiatedcarcinoma	2(5%)	Fibrocystic disease	6(8.2%)
Invasive carcinoma withapocrine differentiation	1(2.5%)	Sclerosing adenosis	2(2.7%)
Invasive carcinoma with plasmacytoid differentiation	1(2.5%)
DCIS	4(10%)
Malignant phyllodes tumour	1 (2.5%)

Discussion

Biopsy is the gold standard investigation for definitive diagnosis of breast lesions but it is invasive and expensive. The relatively lower specificity of breast ultrasound has led to new developments in sonographic technology, and elastography is the most important technique to improve lesion characterization in breast ultrasonography. The role of elastography in breast imaging has been investigated since 2005.While most of the studies have concluded in favour of elastography over conventional ultrasound, Kumm et al.⁸ and Yilmaz et al.⁹ reported lower sensitivity and specificity for sono-elastography when compared with conventional ultrasound.

We intended to study the diagnostic performance of strain elastography when compared with conventional ultrasound with respect to breast lesion characterization by analysing two of the most widely studied elastography parameters; elastography score and strain ratio. Our results showed comparable sensitivity for ES, SR and conventional ultrasonography. However, elastography (ES and SR) showed better overall diagnostic performance with high specificity, diagnostic accuracy and NPV as compared to conventional ultrasound, which is in concordance with other studies.^4,6,10–17

The combined use of ultrasound features and elastography parameters (ES and SR) yielded better results than the individual parameters in each category in agreement with some of the previous studies.^6,10,11 Kumm et al.⁸ suggested that NPV of a diagnostic test should approach 0.98 to confidently characterize a breast lesion as benign.⁸ With the combined use of US, ES and SR, a NPV of 0.97 was obtained in our study.

In our study, elastography yielded better results in categories 3 and 4 A lesions. With the combined use of ultrasound features and elastography parameters, we were able to accurately predict benignity in at least 22 out of a total of 32 BI-RADS 4 category lesions, suggesting that unnecessary biopsy was conducted in these cases. In addition to that, five 4A category lesions were correctly upgraded to 4B or 4C based on the elastography analysis, thereby increasing the diagnostic confidence. These results are in accordance with a meta-analysis conducted by Sadigh et al.,¹⁷ which indicated that ultrasound elastography has the potential to improve the diagnostic accuracy of US.¹⁷ They concluded that in low risk groups, elastography should be performed in positive ultrasonographic results to avoid unnecessary biopsies. Other studies also support these results and came to similar conclusions.^6,11,13,16

Wojcinski et al.¹⁸ analysed BI-RADS 3 lesions with sono-elastography and suggested that these lesions can be categorised into low risk and high risk groups based on the elastography score. Among BI-RADS category 3 lesions, we correctly predicted benignity in 47 out of 51 lesions owing to their elasticity. In addition, two well circumscribed malignant lesions, misclassified as BI-RADS 3 on conventional ultrasonography features were correctly characterized on elastography owing to a high elasticity score and strain ratio and were thus upgraded to category 4.

Apart from the overall performance of elastography, we also tried to compare the individual performance of ES and SR against US. Although a qualitative parameter, ES performed significantly better than SR or US in distinguishing between benign and malignant lesions which is similar to Bojanic et al.⁶ and Yerli et al.’s¹⁹ findings. AUC for elastography score showed a statistically significant difference from conventional ultrasound, with higher specificity, sensitivity and NPV. We also found that the ES of > 3, i.e. score = 4 or 5 has the maximum sensitivity and specificity for the detection of malignancy.

Strain ratio is a semi-quantitative parameter for the measurement of stiffness in a lesion.²⁰ There have been different opinions amongst the researchers on the accuracy of strain ratio. According to some studies, SR is a more effective and objective parameter for the characterization of breast lesions than ES.^{13–15,21,22} However, other studies have reported poor reliability and reproducibility of SR and have found it to be less accurate.^8,19 Yerli et al.¹⁹ concluded that after elastographic score, strain ratio is not needed for the characterization of breast lesions.¹⁹ In our study, the AUC for SR and US did not show any significant difference. Nevertheless, SR was found to be more specific with high NPV than US alone (93% specificity vs. 63%).

Furthermore, different studies have shown variable cut-off values for SR for differentiation of benign versus malignant lesions as described in Table 4. We found maximum sensitivity and specificity at a cut-off value of 3 (sensitivity = 90% and specificity = 93%). A cut-off of 3.5 showed a higher specificity of 95%.

Table 4.

Various studies showing different cut-off values for strain ratio.

Study	Year	SR cut off value
Thomas et al.15	2010	2.45
Gheonea et al.11	2011	3.65
Barr et al.12	2012	4.80
Alhabshi et al.22	2013	5.60
Liu et al.13	2014	4.15
Menezes et al.10	2015	4.72
Bojanic et al.6	2017	3.50
Yilmaz et al.9	2017	4.25

This variation in cut-off value across studies may be attributed to technical factors in acquiring elastography data. Barr et al.²³ described pre-compression as the major limiting factor in obtaining accurate results with both strain and shear wave elastography. They found that pre-compression can increase the overall stiffness of the part being examined with more effect on background fat, thereby reducing the strain ratio and yielding false negative results. For correct measurement of strain ratio, minimum pre-compression should be applied.

The second factor may be the inconsistent placement of the ROI. Selection of equal sized ROI and its placement at the same depth in the lesion and adjacent fat is another important factor for the accuracy of the reading. A third factor is the optimal level of external compression while acquiring elastography data, which is imperative for the accuracy of results. As it is an operator dependent process, it can lead to variable SR values and thus can cause interobserver variations.

In our study, there were 27 false positive lesions on conventional ultrasonography, five on strain ratio and four on elastography score (Table 3). Among these false positive lesions were two fibroadenomata, one sclerosing adenosis, one sclerosing fibroadenoma, and one benign fibroepithelial lesion with sclerosing background. Besides the technical factors in acquiring elastography data, histological make up of breast lesions can also influence the ES and SR values.²⁴ In our study, some of the benign lesions with a significant amount of fibrosis showed high ES > 3 and high strain ratios above our cut-off value 3, thereby leading to false positive results. False negative results on ES were three and SR were four (Table 3). Among the false negative results, two were ductal carcinoma in situ (DCIS), one was mucinous and one was invasive ductal carcinoma. They had elasticity score of 2 or 3 and SR ranging between 2 and 3. Low ES^2,3 and strain ratio were seen (<3) in some malignant lesions due to the inherent softness with no or minimal scirrhous reaction, as in mucinous carcinoma.

Table 3.

Comparison of true positives, false positives, true negatives and false negatives among ES, SR and US with respect to histopathological diagnosis.

Parameters	True positive	True negative	Falsepositive	False negative
US	36	46	27	4
ES	37	69	4	3
SR	36	68	5	4

Our study had some limitations. First is technical. Acquisition and interpretation of strain elastography data are operator dependant leading to interobserver and intraobserver variations, which were not analysed in our study. Second, diagnostic performance of elastography is also affected by the lesion size as suggested by some studies.^6,25 We did not analyse the performance of elastography with respect to lesion size. And finally, the quality of the elastography map depends on the overall breast density and architecture.²⁶ This factor was not evaluated in our study. We propose that these factors should be assessed in larger studies so that strain elastography may be made more quantitative and reproducible.

In conclusion, strain elastography is a useful adjunct to conventional B-mode ultrasound in the characterisation of breast lesions. The combined use of strain elastography and conventional ultrasound can be used to downgrade the substantial numbers of BI-RADS 3 and 4 A category lesions, thereby avoiding unnecessary biopsies and reassuring the physicians for interval follow-ups. Additionally, some of the early cancerous lesions can be better detected on elastography compared to conventional ultrasound and can help in upgrading the lesions to a higher category for biopsies instead of regular follow-up. Elastography score is the most useful predictor of benignity in breast lesions.

Contributors

DS- designed the manuscript, acquired, analysed and interpreted data. Drafted the article and gave the final approval of the version to be published.

SS-Helped in data acquisition.

NGK-helped in conceptualisation, aquisition and revision of the manuscript.

SK-Gave the final approval for the publication.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

Since there is no formal ethical committee in our hospital, our head of the institute has signed a declaration form that the study was performed in accordance with Helsinki Principle.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

DS (Dimpi Sinha).

ORCID iD

Dimpi Sinha https://orcid.org/0000-0002-3903-1547