Since the introduction of SWE and DWI, various clinical applications have been explored. In this study, we investigated the relationship between elasticity and ADC values in breast cancer and found a negative correlation between them. SWE can provide information on tissue stiffness by quantitatively measuring the real-time stiffness of tissue superimposed on a B-mode image quantitatively17. SWE measurement increases in many specific cases, such as in solid tumors as a pathological process or fibrosis as a physiological process18. Tumor stiffness is determined by several factors, including fibrosis, cellularity, and necrosis. Significant collagen deposition, linearization, and bundling lead to extracellular matrix stiffening and remodeling, which corresponds to the malignant transition to invasive cancer by inducing angiogenesis and hypoxia, compromising antitumor immunity, and potentiating tumor cell growth19,20. These changes affect SWE values in breast cancer. ADC values also reflect tumor microstructures, including tumor cellularity, fluid viscosity, membrane permeability, and extracellular matrix stiffness, which drive fibrosis to stiffening of the stroma14.
Matsubayashi et al.16 reported that US elastographic strain score and MRI diffusion were significantly correlated with fibrotic changes in breast disease based on pathologic examination. They classified the elastographic strain score as 1–5 points according to the strain map pattern, whereas we measured the objective SWE (Emean and Emax) of breast cancers. Recently, Orguc et al.15 reported that the SWE and ADC values were correlated in 147 benign and malignant breast lesions. In contrast, we focused on breast malignancies to evaluate the correlation between SWE and ADC values, which may be affected by microstructural changes in malignancies. In addition, we compared the SWE and ADC values according to the imaging characteristics of gray-scale US and DCE-MRI. Our results demonstrated a weak negative correlation between stiffness measured using SWE and ADC values in breast cancers. The pathological explanation of this correlation could be explained by tumor cellularity, degree of stromal fibrosis, extracellular matrix stiffness, or tumor to stroma ratio in breast cancer influencing the SWE and ADC values; these microstructural changes in breast cancer result in a correlation between these values. In addition, tumor stiffness may correspond to diffusion restrictions in breast cancer.
Our results indicated that SWE values were significantly higher in breast cancers with posterior enhancement, vascularity, and washout kinetics. Posterior enhancement is the phenomenon that sound transmission is unimpeded in its passage through the mass21. It is well known that high cellularity or tumor necrosis is associated with posterior enhancement and identified in 24–41% of triple-negative breast cancers22. Additionally, high-grade breast cancer is linked to higher chance of posterior enhancement23. Vascularity and enhancement kinetics reflect angiogenesis, which plays important role in tumor growth and progression and is mediated by the tumor microenvironment, including extracellular matrix stiffening and mechanical forces24. Among the enhancement kinetics, washout kinetics on the delayed phase are associated with poorer clinical outcomes25. Our findings suggest that imaging characteristics associated with aggressive biology and poor clinical outcomes are also related to higher elasticity. Meanwhile, the ADC values were lower in breast masses with irregular shape and not circumscribed margin. Larger studies are required to validate our findings.
Using SWE, the mean Emean value of the breast cancers in our study was determined to be 167.7 ± 75.0 kPa, which is comparable to the range of 133–153 kPa reported in previous studies, and higher than the cutoff values of 72–100 kPa used to for distinguishing between malignant and benign lesions4,26. Our study showed higher SWE values for higher T stages/larger tumor sizes, which are poor prognostic factors, consistent with previous studies6,7,27. Triple-negative breast cancer had the highest Emean and Emax values, whereas luminal A breast cancer had the lowest Emean and Emax values. Biophysical and biochemical assessments revealed that extracellular matrix stiffness, immune infiltrate, and tumor progression differed according to tumor subtype. Triple-negative cancers have poor clinical outcomes and are associated with aggressive histology28. Triple-negative cancers have yielded controversial results regarding elasticity. Several previous studies have found that triple-negative cancers and ER/PR negativity are correlated with higher SWE values because they have higher heterogeneous extracellular stiffness, which reflects an increased number of infiltrating immune cells and macrophages, more linearized collagen, and invasion signaling, which is consistent with our results7,27,29, whereas others have reported that triple-negative cancers are less stiff than other breast cancers30.
The ADC value from DWI reflects cellular density and quantifies water diffusion, and its major strength is that it provides a quantitative measure of the observed diffusion restriction. We found a mean ADC value of 0.982 × 10− 3 mm2/s for breast cancers and a maximum value of 1.520 × 10− 3 mm2/s, which is comparable to the previously reported ADC cutoff values of 1.1–1.6 × 10− 3 mm2/s for distinguishing between benign and malignant lesions31,32. Several studies have investigated the relationship between ADC values and pathological characteristics and have shown conflicting results. Some studies have found that lower ADC values are associated with larger tumor size, higher histological grade, and invasiveness33–35, whereas others have found no significant relationship12,14,36. Several studies showed that HER2-enriched tumors have higher ADC values, whereas ER-positive tumors have lower ADC values than ER-negative tumors11. However, a recent meta-analysis found that the ADC cannot discriminate between molecular subtypes, which suggests that the ADC cannot be used as a surrogate marker for disease stage or proliferation activity37. In our study, there were no significant differences between the ADC values and different pathological types, T stages, or molecular subtypes. These results may be attributed to relatively small sample sizes.
Our study had several limitations. First, it was a retrospective study conducted at a single institution with a relatively small number of breast cancer cases. Further, we included patients who underwent both SWE and DWI before breast cancer surgery, which might have caused a selection bias. Second, breast cancers are heterogeneous in stiffness and cellularity, and the precise areas measured using SWE and DWI are likely to differ. However, it was inevitable to acquire same areas of the tumor because the modalities were different. To overcome these issues, we attempted to acquire the most representative part of the tumor by measuring SWE and ADC in the area with the largest diameter. Third, we did not evaluate the inter-observer agreement of SWE and ADC values. Fourth, although SWE was performed using the same US machine by a single radiologist to avoid interoperator variability, patient-related or clinical factors might have influenced the quality of the images and SWE values. Lastly, we did not correlate SWE or ADC values with histopathological findings such as collagen, extracellular matrix, or the degree of stromal fibrosis in breast cancers, which could help explain the probable cause of the relationship between SWE and ADC values. However, the purpose of our study was not to determine whether there is an exact point-to-point correlation between imaging and pathological findings but to determine the correlation between the two values measured by different modalities in breast cancers. Larger dedicated studies analyzing pathological correlations are necessary to validate our findings.
In conclusion, SWE stiffness and ADC values were negatively correlated in breast cancer. SWE values significantly correlated with tumor size and were higher in triple-negative subtypes and imaging characteristics associated with aggressive biology.