Imaging examinations, especially molybdenum target radiography, magnetic resonance imaging, and ultrasonography play an important role in the early screening and diagnosis of breast diseases. Over the past several years, studies outside of China have suggested that large-scale breast cancer screening programs can reduce the overall and early breast cancer mortality rates by 20% and 60%, respectively . However, in comparison to women of other ethnicities, Chinese women generally have relatively smaller breast volumes with higher proportions of having a dense breast tissue; these characteristics can reduce the sensitivity of mammography for identifying malignant breast lesions. In these cases, US is a more effective method for characterizing suspicious lesions .
Conventional US can clearly show a variety of breast lesion characteristics, including the location, number, size, shape, orientation, perimeter, internal echo, rear features, calcification, blood supply, and associated axillary lymph nodes. However, in clinical practice, 2D US manifestations of benign and malignant nodules sometimes share overlapping characteristics, especially in patients with small breast tumors. The BI-RADS classification, which standardizes breast ultrasonography reporting worldwide , has been shown to improve the sensitivity of identifying malignant masses; however, the false-positive rate remains high .
Based on years of clinical experience, we believe that the biological characteristics of small breast cancers are less commonly manifested and that signs of malignancy in these small tumors are more difficult to be observed using 2D US imaging. Even color Doppler imaging cannot adequately detect obvious differences in the blood flow for benign nodules, making differential diagnosis is even more difficult. In addition, the pathological characteristics of breast cancer tissues are diverse, potentially leading to false positives and false negatives. For example, some in situ cancers with small and atypical nodules do not display hyperechoic halos or burr signs, and can be misdiagnosed as benign nodules. In this study, three cases of carcinoma in situ were diagnosed as benign nodules, and one case of CEUS and SWE suggested the possibility of malignancy. Therefore, BI-RADS classification was upgraded from category 4A to 4B. Moreover, some small invasive ductal, mucinous, and papillary carcinomas manifest with clear boundaries, few lobes, and parallel growth, leading to false negatives. In this study, two cases of invasive ductal carcinoma < 1 cm were diagnosed as benign nodules, including one case of three-negative carcinoma with a diameter of 0.9 cm. SWE suggested that the SWV value was lower than the truncation value, CEUS suggested the presence of malignant nodules, and finally, the BI-RADS classification remained unchanged from category 4A. The other was luminal type A. SWE suggested that the SWV value was lower than the truncation value; CEUS also suggested the presence of benign nodules, and the BI-RADS classification decreased from category 4A to 3. Finally, some sclerosing adenoses, intraductal papillomas with inflammation, and other benign lesions exhibited obscure boundaries, leading to false infiltration and false positives. In this study, using US, 35 cases of benign nodules were diagnosed as being malignant. Therefore, the use of conventional ultrasonography, which relies on the recognition of distinctive morphological features, can be problematic during the evaluation of small breast nodules.
In addition to morphological features, other tumor characteristics have been evaluated for their applicability to imaging-based diagnoses. For example, previous studies have shown that angiogenesis plays an important role in tumor growth and metastasis . Tumor blood flow has been evaluated using Doppler US with some success; however, this modality can only identify a blood flow signal above the threshold of large vessels and the wall filter . Conversely, real-time CEUS can provide more accurate information regarding the morphology and distribution of the blood vessels associated with tumors . Moreover, SWE can quantitatively evaluate the hardness of breast nodules [17,18]. Therefore, conventional US combined with CEUS and SWE techniques can comprehensively evaluate nodules based on their shape, micro-blood flow, and hardness to improve diagnostic efficacy.
CEUS is an advanced technique for microperfusion imaging using a safe contrast medium. It can dynamically provide a real-time display of the microperfusion of tumors, lymph nodes, and surrounding tissues, and it plays significant roles in the diagnosis and targeted therapy of breast diseases, detection of metastatic sentinel lymph nodes, and evaluation of neoadjuvant chemotherapy efficacy. CEUS can qualitatively characterize the benign and malignant lesions by identifying the homogeneous and centripetal enhancement of benign lesions. In addition, it can quantitatively characterize lesions by creating time-intensity curves and obtaining a series of quantitative parameters, including the rise time, peak time (time to peak), peak intensity, mean transit time, and the AUC.
The present study found that most fibroadenomas and intraductal papillomas manifested with true capsules or pseudocapsules caused by expansive growth; accordingly, when there was high enhancement on CEUS, the boundary was clear and the enhancement was well distributed. In contrast, malignant lesions of the breast often lacked a capsule, while the boundary and size of the tumor and the shape of nutrient angiography, could only be observed after enhancement. As angiogenesis is a risk factor for invasion and metastasis of solid tumors, there are generally many proliferative and active cells at the perimeter of malignant tumors, and numerous abnormal capillary networks with disordered structures and increased microvessel densities. At the same time, perfusion disruptions can lead to increased microcirculation flow and velocity . In addition, the peripheral regions of malignant breast tumors are often associated with breast hyperplasia and precancerous lesions at different stages. With the progression of these precancerous lesions to breast cancer, neovascularization and blood vessel density could also increase .
In this study, adenoses generally manifested without pseudocapsules and exhibited an irregular shape after enhancement, which was often low or equally distributed, with a focus to remain unchanged, become narrowed, or become completely integrated with the surrounding glands after enhancement. Further, few nutrient vessels and filling defects were manifested. These features can be helpful for differential diagnosis; however, some special adenoses exhibit uneven enhancement and unclear boundaries and can, therefore, easily be misdiagnosed as malignant nodules. Some inflammatory lesions also showed malignant signs after enhancement, including uneven high enhancement, irregular shapes, and unclear boundaries, which have likely resulted from irregular infiltration of inflammatory cells into the surrounding tissue.
Real-time SWE can indicate differences in tissue hardness by measuring the propagation velocity of shear waves in tissues, and can also qualitatively and quantitatively distinguish the benign from malignant lesions. The elastic coefficient or hardness of the tissue is closely associated with the biological characteristics of lesions. The stroma of a benign tumor, such as breast fibroadenoma, is rich in loose mucopolysaccharides; thus, its hardness is reduced in comparison to malignant tumors like invasive ductal carcinomas, in which the stroma is denser and harder due to fibrous tissue components . In general, tumors are softer when they have a higher proportion of parenchyma than the stroma. The tumor tissues can also soften when undergoing necrosis and harden when calcareous deposition or bone formation occurs. Real-time SWE is a relatively easy, noninvasive, and objective method to evaluate the tissue hardness. Interestingly. this study and others, have demonstrated that it can effectively be used to differentiate the benign from malignant breast tumors.
In line with our previous study, we found that SWE had a high diagnostic sensitivity and specificity for the BI-RADS category 4 nodules and small breast tumors. These findings were also consistent with those of other studies, performed in China and elsewhere [22,23]. Many studies have shown that tissue density information obtained by SWE can predict the degree of vascular infiltration, which is a predictor of lymph node metastasis [24,25]. Tumor cells can infiltrate the surrounding stroma and cause changes to the connective tissue, increasing collagen cross-linking and the corresponding density of the surrounding tissues. Using color gradients, SWE can demonstrate the hardness of areas surrounding lesions, with high-density areas displaying "hard ring signs" . Unfortunately, this technique can also lead to misdiagnosis, as some malignant lesions undergo liquefactive necrosis, resulting in decreased SWV values and false-negative diagnoses. The SWV values for intraductal carcinomas with low tumor cell atypia, reduced proliferation of the fibrous tissue, and no obvious infiltration into the surrounding tissues has also been shown to be below the cut-off value. Some sclerosing benign breast lesions may also lead to increased elastic modulus of the tissues, resulting in false-positive diagnoses.
In our study, the combined use of CEUS, SWE, and BI-RADS led to adjustments in the BI-RADS classification for some breast nodules, with improvements in the diagnostic accuracies for benign and malignant breast nodules. Sclerosing adenoses were most commonly identified to be false positives, with some cases showing irregular morphologies due to interstitial fiber hyperplasia that was sometimes mixed with inflammation. In these instances, the SWV value was higher than the cut-off value and CEUS showed uneven regions of high contrast enhancement. The malignant features of small breast carcinomas, identified as false negatives, were not as obvious on 2D ultrasonography, showing only large lobulation, homogeneous echo patterns, and no changes or enhancement in posterior features. The US images resembled those of benign tumors, with SWE values lower than the cut-off value, and CEUS showing only uniformly low contrast enhancement. Therefore, it is necessary to comprehensively analyze many images for nodules with these features, with a recommended close follow-up examination. In addition, patients aged < 60 years with a higher risk of malignancy due to family history should be closely followed-up, and further puncture biopsies should be performed where necessary.
The BI-RADS classification has also flaws, especially in patients with category 4 nodules (with a malignant probability > 2%, but < 95%) . In the United States, most cases of BI-RADS category 4 lesions (69–95%) undergo puncture biopsies, although only 22–33% of these lesions are malignant. A meta-analysis of studies, including cases from Europe and the United States, showed that the overdiagnosis rate of breast cancer lesions using molybdenum target mammography was 52% with the current BI-RADS classification . In the present study, 120 nodules were initially evaluated as BI-RADS category 4A, with 67 cases adjusted to BI-RADS category 3 after consideration of the CEUS and SWE results. This finding indicated that 55.8% (67/120) of BI-RADS 4A nodules would have undergone unnecessary puncture biopsies after conventional US if not combined with the CEUS and SWE results.
The current study had several limitations. First, as this is a retrospective study, the potential bias in the selection of the participants could not be eliminated. Second, the sample size was small; therefore, studies on larger datasets with long-term follow-up periods are required.