Diagnostic value of contrast-enhanced ultrasound and shear-wave elastography for small breast nodules

Background The study aims to evaluate the diagnostic efficacy of contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE) in detecting small malignant breast nodules in an effort to inform further refinements of the Breast Imaging Reporting and Data System (BI-RADS) classification system. Methods This study retrospectively analyzed patients with breast nodules who underwent conventional ultrasound, CEUS, and SWE at Gongli Hospital from November 2015 to December 2019. The inclusion criteria were nodules ≤ 2 cm in diameter with pathological outcomes determined by biopsy, no prior treatments, and solid or predominantly solid nodules. The exclusion criteria included pregnancy or lactation and low-quality images. Imaging features were detailed and classified per BI-RADS. Diagnostic accuracy was assessed using receiver operating characteristic curves. Results The study included 302 patients with 305 breast nodules, 113 of which were malignant. The diagnostic accuracy was significantly improved by combining the BI-RADS classification with CEUS and SWE. The combined approach yielded a sensitivity of 88.5%, specificity of 87.0%, positive predictive value of 80.0%, negative predictive value of 92.8%, and accuracy of 87.5% with an area under the curve of 0.877. Notably, 55.8% of BI-RADS 4A nodules were downgraded to BI-RADS 3 and confirmed as benign after pathological examination, suggesting the potential to avoid unnecessary biopsies. Conclusion The integrated use of the BI-RADS classification, CEUS, and SWE enhances the accuracy of differentiating benign and malignant small breast nodule, potentially reducing the need for unnecessary biopsies.


INTRODUCTION
Breast cancer is the most frequently diagnosed cancer among women and the second leading cause of cancer-related, contributing significantly to morbidity (Siegel et al., 2022;Sung et al., 2021).The asymptomatic detection of breast abnormalities during screenings

Study design and patients
This retrospective study enrolled all patients with breast nodules who underwent conventional ultrasound, CEUS, and SWE at Gongli Hospital between November 2015 and December 2019.The Ethics Committee of Gongli Hospital approved this study (#[2020] Provisional Trial No. ( 003)).Given its retrospective design, the requirement for individual consent was waived by the committee.All patient details have been de-identified.The reporting of this study conforms to the STROBE guidelines as per the recommendation (von Elm et al., 2007).
The inclusion criteria encompassed patients who met the following criteria: (1) a breast nodule with a diameter of ≤2 cm with pathological outcomes based on the results of surgical or needle biopsy, (2) no prior treatment for a breast nodule before ultrasonography, and (3) a solid or predominantly solid breast nodule (with the cystic component constituting <25% of the total volume).The breast density of the patients included in this study comprises Type B, Type C, and Type D as determined by ultrasound characteristics.These types reflect a range of breast tissue compositions, including predominantly fibrous (Type B), heterogeneous density with both fibrous and glandular elements (Type C), and predominantly glandular tissue (Type D), which can influence the sensitivity of imaging techniques and the interpretation of findings.
Conversely, the exclusion criteria were (1) pregnancy or lactation and (2) low-quality breast nodule images that were unsuitable for analysis, including cases with blurriness on conventional ultrasound or inconclusive SWE measurements.
For clarity, patients with BI-RADS category 1 lesions, indicating no abnormalities, were excluded from the study.Additionally, patients with BI-RADS category 2 lesions were also excluded.The rationale for this exclusion is that category 2 nodules are typically benign and they often require no further investigation beyond regular follow-up.It is only when these nodules exhibit changes that might warrant a change in the BI-RADS classification that additional imaging or biopsy is considered.A visual representation of the patient selection process is detailed in Fig. 1.

Data collection and imaging examinations
Information on age, tumor size, location, shape, orientation, margins, echo patterns, posterior acoustic features, calcification, vascularity, and lymph node metastasis was retrieved from the patients' medical records.The multimodality ultrasound examinations were all performed on the same day.

Conventional ultrasound
Operators recorded comprehensive details regarding nodular characteristics, encompassing location, size, shape, orientation, margin, echo pattern, posterior acoustic features, calcification, and vascularity.Subsequently, lesions were classified according to the BI-RADS classification system.In cases in which multiple nodules were present, the nodule with the highest BI-RADS classification was included in the study.If two nodules held the highest BI-RADS classification, both were included concurrently.

SWE
During the study period, a Siemens Acuson S3000 ultrasound diagnostic apparatus (Siemens Medical Solutions, Mountain View, CA, USA) equipped with SWE imaging software was employed for SWE.SWE was conducted when the gray-scale ultrasound indicated that the maximum diameter of the lesion and the image clarity was optimal.The SWE sampling frame size was adjusted to be at least twice the size of the nodules, and patients were instructed to briefly hold their breath after achieving image stability.The SWE speed mode was utilized to directly derive the shear-wave velocity (SWV) across the two-dimensional spatial distribution of the SWE imaging map.The SWV range was gradually fine-tuned (with a maximum of 10.0 m/s) when the interior regions of the nodules displayed red or yellow hues, whereas the surrounding areas appeared blue or green.Multiple regions of interest (typically 5-7) were strategically positioned within various areas within the nodules (upper, lower, middle, and periphery at the highest and lowest speeds).SWV measurements were taken within the effective measurement areas, and the average SWV (m/s) was subsequently determined for each nodule.

CEUS
During the study period, a Philips EPIQ 5 ultrasound diagnostic apparatus equipped with CEUS software (Philips Medical Systems, Bothell, WA, USA) was used.For CEUS, sections exhibiting robust blood flow, prominent blood vessels, or irregular shapes were selected.Areas featuring substantial calcification accompanied by broad sound shadows were intentionally avoided.The focal point was positioned behind the nodule using a mechanical index of 0.07.The contrast agent SonoVue (25 mg in five mL of 0.9% sodium chloride, Bracco SpA, Milan, Italy) was administered per the standard procedure.The nodule's dynamic perfusion process was observed for at least 3 min.During CEUS, nine distinct variables were assessed (Luo et al., 2016)

Imaging analysis
All SWE image acquisitions and subsequent data analyses were performed by two radiologists with more than 3 and 10 years of expertise, respectively, in SWE and breast ultrasonography.CEUS images were evaluated by two radiologists with more than 5 and 10 years of proficiency, respectively, in CEUS and routine ultrasound examinations.Each ultrasound image was reviewed and confirmed by two ultrasound specialists not involved in the acquisition of the contrast images.The contrast characteristics of the lesions were categorized following consensus agreement.Prior to image analysis, these two ultrasound specialists were not privy to the patients' clinical data, ensuring an unbiased evaluation process.This approach ensured consistent assessment of CEUS images by the two radiologists.Disagreements between the radiologists were resolved through joint re-evaluation of the imaging features.This collaborative process ensured that any discrepancies were resolved in a manner that maintained the integrity and reliability of the study findings.
To determine the most accurate classification for breast nodules, an integrated multimodal imaging approach was utilized.Initially, each nodule was given a preliminary classification based on the BI-RADS system.Subsequently, nodule vascularity was assessed using CEUS, and any nodule exhibiting at least two malignant features was classified as malignant.The classification was further refined using SWE, with nodules having SWVs of 3.7 m/s or higher being considered malignant.The final categorization was achieved by combining the results of the initial BI-RADS classification with the findings of CEUS and SWE.In cases of disagreement between CEUS and SWE, the BI-RADS classification was either upgraded, downgraded, or retained (Fig. 1).The resulting integrated methodology provided an enhanced diagnostic platform, amalgamating the insights of BI-RADS, CEUS, and SWE.The SWE classification cutoff 3.7 m/s is derived from our team's clinical experience and a detailed analysis of patient data from the hospital.This value was established through receiver operating characteristic (ROC) curve analysis, which provided the highest accuracy in distinguishing between benign and malignant nodules.

Statistical analysis
The statistical analysis was performed using SPSS 22.0 (IBM, Armonk, NY, USA) and MedCalc 19.0.7 (MedCalc Software bvba, Ostend, Belgium).Continuous variables were reported as means ± standard deviations or ranges, and comparisons were made using the independent-samples t -test.Categorical data were presented as n (%) and analyzed using the chi-squared test or Fisher's exact test.The agreement between the two radiologists for CEUS and SWE evaluations was determined using the interclass correlation coefficient (ICC), with values close to 1 indicating excellent reliability.To assess the diagnostic efficacy of classifying small breast nodules, ROC curves were employed for the four diagnostic methods (BI-RADS, CEUS, SWE, and the combined method).Areas under the curve (AUCs) were computed to determine the diagnostic performance of the four methods.For statistical evaluation, the Cochran Q-test and z-test were utilized.The optimal cutoffs were derived from the ROC analysis, with subsequent calculation of sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy (ACC).Statistical significance was defined as a two-sided P-value of less than 0.05.

Clinical data and pathological findings
In this study, of the 676 initially assessed patients, 302 met the inclusion criteria, and 305 nodules were analyzed because three patients had two nodules with the same highest BI-RADS classification.Among these, 113 nodules (37.0%) were malignant, and 192 (63.0%) were benign.The mean age of the patients was 49.2 ± 16.4 years.The benign nodules comprised various pathologies, most commonly fibroadenoma (43.2%), adenopathy (21.4%), and adenopathy with fibroadenoma (20.3%).The malignant nodules were mainly invasive ductal carcinoma (69.0%), followed by ductal carcinoma in situ and papillary carcinoma (9.7% each).

Diagnostic efficacy
The BI-RADS classifications of the breast nodules are outlined in Table 2.The determined cutoff for the BI-RADS classification system was category 4B.Correspondingly, this yielded   Interrater reliability, as assessed using ICC, indicated excellent agreement between the two radiologists for both CEUS (ICC = 0.91, 95% confidence interval (CI) [0.89-0.93])and SWE (ICC = 0.89, 95% CI [0.86-0.91]).The distinct characteristics indicative of potential malignancy in breast nodules identified by CEUS are presented in Table 3. CEUS demonstrated the capacity to identify malignant nodules when at least two of the nine suspicious malignant signs were concurrently present.In this scenario, the ensuing SEN, The diagnostic efficiency of SWE was determined using the mean SWV.Malignant nodules exhibited a mean SWV of 5.2 ± 1.6 m/s, which was significantly higher the value observed for benign nodules (3.1 ± 1.1 m/s, P < 0.001).Employing ROC curve analysis, the optimal cutoff for SWV was 3.7 m/s.Consequently, the resulting SEN, SPE, PPV, NPV, ACC, and AUC were calculated as 86.7%, 82.8%, 74.8%, 91.4%, 84.3%, and 0.848, respectively.
When CEUS or SWE alone was combined with the BI-RADS classification in diagnosing benign nodules, the BI-RADS classification remained unaltered.Nonetheless, the AUC for this combined diagnosis was 0.758, indicating lower performance compared to the individual BI-RADS classification, SWE, and CEUS.Conversely, the combination of CEUS and SWE led to a one-category increase and decrease in the BI-RADS classification for malignant and benign nodules, respectively.This combined diagnostic approach yielded SEN, SPE, PPV, NPV, ACC, and AUC of 88.5%, 87.0%, 80.0%, 92.8%, 87.5%, and 0.877, respectively.
Significant differences were noted among the four diagnostic methods, as indicated by the Cochran Q-test (Cochran's Q = 19.573,P < 0.01).The AUCs for the diagnostic efficacy of BI-RADS, CEUS, SWE, and the combined method (CEUS + SWE + BI-RADS) were 0.784, 0.853, 0.848, and 0.877, respectively.In the statistical comparison of the combination diagnostic model with BI-RADS, CEUS, and SWE when utilized individually, P-values of <0.001, 0.012, and 0.017, respectively, were obtained.These results suggest that the combination diagnostic approach is significantly more effective than the individual methods (Tables 4-5 and Fig. 3).Implementing this combined diagnostic approach resulted in the reclassification of 55.8% (67/120) of the BI-RADS 4A nodules as BI-RADS 3.These reclassified nodules were subsequently confirmed as benign through pathological assessment, suggesting that unnecessary biopsy procedures could potentially be avoided for such nodules.

DISCUSSION
This study assessed the potential of CEUS and SWE to distinguish between benign and malignant small breast nodules.The findings indicate that CEUS and SWE could serve as supplementary techniques to enhance the accuracy of the BI-RADS classification for small breast nodules.The combination of CEUS, SWE, and BI-RADS has the potential to enhance the identification of small malignant breast nodules and subsequently reduce the necessity for biopsies.
Through the utilization of CEUS, this study revealed distinct characteristics among fibroadenomas, intraductal papillomas, and malignant breast lesions.Malignant breast lesions often lack capsules, and they feature disorganized capillary networks and increased microcirculation on CEUS, distinguishing them from benign lesions such as fibroadenoma and intraductal papilloma (Chen et al., 2023;Wang et al., 2023).Moreover, the peripheries of malignant breast tumors frequently overlap with regions of breast hyperplasia and various stages of precancerous lesions.Adenosis and inflammatory lesions can exhibit malignancy-like features, such as uneven enhancement and irregular shapes, on CEUS, potentially leading to misdiagnosis (Huang et al., 2019).
Benign tumors, such as breast fibroadenomas, possess stroma with abundant loose mucopolysaccharides, contributing to their reduced hardness compared to malignant tumors such as invasive ductal carcinomas, which are characterized by denser and harder stromal structures because of their fibrous tissue constituents (Aouad et al., 2017).The real-time SWE technique offers a relatively straightforward, noninvasive, and objective approach for assessing tissue hardness.Notably, this study consistently demonstrated the strong diagnostic performance of SWE in terms of SEN and SPE for both BI-RADS 4 nodules and small breast tumors, corroborating prior research findings (Ko et al., 2010;Park et al., 2015).Tissue density data obtained by SWE can predict the extent of vascular infiltration, a key determinant of lymph node metastasis (Celebi et al., 2015;Wojcinski et al., 2012).
It combined CEUS, SWE, and BI-RADS to fine-tune the classification of certain breast nodules.This combined approach resulted in enhanced diagnostic accuracy for both benign and malignant breast nodules.Notably, the study demonstrated that using CEUS and SWE to either downgrade (when both indicators are negative) or upgrade (when both indicators are positive) the BI-RADS classification by one category yielded a superior AUC compared to any of the three methods alone.Significantly, this amalgamated method enabled the reclassification of 55.8% of BI-RADS 4A nodules as BI-RADS 3, all of which were subsequently confirmed to be benign upon pathological examination.This underscores that biopsy could have been avoided for 67 of 120 nodules.Among the falsely identified cases, sclerosing adenoses were the most prevalent, displaying irregular morphologies attributable to interstitial fiber hyperplasia often accompanied by inflammation.These instances corresponded with elevated SWVs exceeding the established threshold coupled with variable regions of pronounced contrast enhancement on CEUS.Conversely, small breast carcinomas that escape detection despite exhibiting malignant features were not as conspicuous on two-dimensional ultrasound, merely displaying significant lobulation, uniform echo patterns, and the absence of posterior feature changes or enhancement.These ultrasound representations bore resemblance to benign tumors, with SWE values below the cutoff and CEUS revealing uniform, low-contrast enhancement.Consequently, a comprehensive analysis of multiple images is imperative for nodules with these attributes, necessitating vigilant monitoring.Furthermore, individuals younger than 60 who have an elevated malignancy risk because of familial history should undergo close surveillance, with additional puncture biopsies performed as deemed necessary (Smith, Cokkinides & Brawley, 2012).
The BI-RADS classification system is not exempt from shortcomings, which are particularly evident in cases involving BI-RADS 4 nodules (in which the probability of malignancy ranges from >2% to <95%) (Jørgensen & Gøtzsche, 2009).In the context of this study, of the 120 nodules initially classified as BI-RADS 4A, 67 were subsequently reclassified as BI-RADS category 3 following the integration of CEUS and SWE results.The diagnostic approach proposed in this study holds the potential to avoid unnecessary biopsies, thereby reducing the associated morbidity linked to breast nodule screening.
Combining ultrasonography modalities for assessing BI-RADS 4 breast lesions continues to be of interest, with studies advocating for various combinations to achieve optimal accuracy.As evident from the recent literature, the amalgamation of ultrasound with two-dimensional SWE and CEUS has displayed considerable promise, especially in studies by Chen et al. (2022) and Liu et al. (2019), which reported AUCs of 0.974 and 0.973 respectively (Table 6).Such high AUCs indicate a substantial diagnostic accuracy.The amalgamated study using a unique combination of BI-RADS, CEUS, and SWE revealed a similar trend, although the AUC was slightly lower at 0.877.Nonetheless, combined modalities enhance the diagnostic precision in assessing BI-RADS 4 lesions.This underscores the potential of these combined techniques as pivotal tools in breast lesion assessment, thus informing clinical decision-making and potentially leading to better patient outcomes.
Several limitations of this study must be acknowledged.First, its retrospective design inherently carries the risk of selection bias, as the study used pre-existing records that might not have captured all relevant variables uniformly (Hall, Kea & Wang, 2019).Second, the study was potentially subject to inherent biases related to the interpretation of imaging results despite efforts to ensure blinded assessments.Additionally, the study was conducted at a single institution, which could limit the generalizability of the findings to other settings with different patient demographics or varying levels of access to imaging technologies.Finally, although the combination of CEUS and SWE led to improved diagnostic accuracy, the cost and availability of these technologies might pose barriers to their widespread adoption, particularly in low-resource settings (Dan et al., 2023).Future prospective studies with larger, more diverse populations and multicenter collaborations are necessary to validate these findings and explore the cost-effectiveness and practical implementation of integrating CEUS and SWE into routine clinical practice.The findings of this study have significant implications for clinical guidelines and practices, particularly in resource-limited settings in which access to advanced imaging technologies such as CEUS and SWE could be restricted (Dan et al., 2023).The enhanced diagnostic accuracy achieved by combining CEUS and SWE with the BI-RADS classification system suggests a potential paradigm shift in the management of small breast nodules.However, it is crucial to consider the feasibility and accessibility of these technologies in diverse clinical settings.In regions where these advanced imaging modalities are not readily available, alternative strategies must be developed to ensure that patients receive accurate and timely breast cancer diagnoses (Bonsu & Ncama, 2018;Broach et al., 2016).Future studies should focus on adapting these findings to simpler, more widely available diagnostic tools to ensure broad applicability and minimize disparities in breast cancer care.

CONCLUSIONS
The integrated diagnosis using multiple ultrasound techniques (BI-RADS with conventional ultrasound, CEUS, and SWE) displayed an enhanced capability to differentiate benign and malignant breast nodules.CEUS and SWE might effectively serve as supplementary tools to enhance the clarity of the BI-RADS classification for smaller benign nodules, thereby refining the management of BI-RADS categorization for this subset of cases.

Figure 1
Figure 1 Flowchart of patient selection.

Figure 2 (
Figure 2 (A) An irregular and uncircumscribed nodule classified as BI-RADS 4A.(B) CEUS revealed no significant enhancement, and the volume decreased after enhancement.(C) The average SWV on SWE was 2.8 m/s, which was below the cutoff, indicating that the texture of the nodules was soft.After combining BI-RADS, CEUS, and SWE, the BI-RADS category was downgraded to BI-RADS 3. The final pathological result was breast adenopathy.(D) The nodule was not circumscribed and not parallel, and it was classified as BI-RADS 4A.(E) CEUS displayed high enhancement and an increased volume after enhancement.(F) The average SWV on SWE was 4.1 m/s, which exceeded the cutoff, indicating that the nodule was hard.After combining BI-RADS, CEUS, and SWE, the BI-RADS category was upgraded to BI-RADS 4B.The final pathological result was ductal carcinoma in situ.BI-RADS, Breast Imaging Reporting, and Data System; SWV, shear-wave velocity; SWE, shear-wave elastography; CEUS, contrast-enhanced ultrasound.Full-size DOI: 10.7717/peerj.17677/fig-2

Figure 3
Figure 3 Analysis of the receiver operating characteristic curves of the four methods.Full-size DOI: 10.7717/peerj.17677/fig-3

Table 4 Comparison of the diagnoses of malignant nodules based on the four examination methods.
Notes.BI-RADS, Breast Imaging-Reporting and Data System; CEUS, contrast-enhanced ultrasound; SWE, shear-wave elastography.

Table 5 Diagnostic efficacy of the four examination methods.
Notes.SEN, sensitivity; SPE, specificity; PPV, positive predictive value; NPV, negative predictive value; ACC, accuracy; AUC, area under the receiver operating characteristic curve; CI, confidence interval; BI-RADS, Breast Imaging Reporting and Data System; CEUS, contrast-enhanced ultrasound; SWE, shear-wave elastography.

Table 6 Comparative analysis of combined ultrasonography modalities in assessing breast lesions.
US, ultrasonography; 2D-SWE, 2D shear wave elastography; CEUS, contrast enhanced ultrasonography; BI-RADS, Breast Imaging-Reporting and Data System; AUC, areas under the curves.