Application Study Of Contrast-enhanced Ultrasound In Diagnosis And Evaluation Response To Chemotherapy Of Breast Cancer

Part1Association of contrast-enhanced ultrasound characteristics with biological prognostic factors and microvessel density in breast cancerObjective:Breast cancer is a vascular-dependent lesion, and its growth, infiltration and metastasis are closely related to the neovascularization. The development of contrast-enhanced ultrasound (CEUS) technology make it possible to reveal the tumor microcirculation. The aim of the study was to analyse the CEUS enhancement characteristics of invasive ductal carcinoma, and to investigate the association of CEUS enhancement characteristics and blood perfusion parameters with prognostic factors and microvessel density (MVD), which can be helpful to evaluate the tumor angiogenesis and prognosis.Methods:From October2010to February2012,45consecutive breast cancer patients were studied by CEUS. All patients were diagnosed with invasive ductal carcinoma on the basis of biopsy or surgery results. The tumor size was an average of (30.5±18) mm, ranging from9to86mm. Color Doppler Ultrasound Philips iU22with L9-3and L5-1probes were used in this study. The contrast agent used was SonoVue (Bracco, Italy). All patients accepted an elbow intravenous bolus injection of4.8ml. Breast cancer enhancement characteristics at CEUS imaging, including enhancement pattern, internal homogeneity, perfusion defect, enhancement order, margin, and penetrating vessels was analyzed. QLAB software was used with CEUS imaging to obtain the time-intensity curve of the periphery and inside region of tumor, and blood perfusion parameters (rising time, RT; time to peak, TTP; peak intensity, PI; wash-in slope, WIS; mean transit time, MTT) was evaluated. Pathologic prognostic factors, including estrogen receptor (ER) and progesterone receptor status (PR), c-erb-B2, p53, and Ki-67expression were determined by immunohistochemical staining, which considered positive when membranous or nuclear staining was observed. And the MVD were count. Association of CEUS enhancement characteristics with prognostic factors and MVD results was analyzed.Results:1. CEUS enhancement characteristics of breast cancer. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, blood perfusion was observed in43cases (95.6%). The45malignancies displayed heterogeneous enhancement in25cases (55.6%), homogeneous enhancement in14cases (31.1%), peripheral enhancement in4cases (8.9%). Local blood perfusion defect was observed in27cases (60%), irregular enhancement shape in37cases (82.2%), centripetal enhancement in25cases (55.6%), penetrating vessels in32cases (71.1%) and poorly-defined margin in34cases (75.6%),2. CEUS blood perfusion parameters analysis. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, the time-intensity curve of43cases was characterized as ascend rapidly and drop slowly or rapidly. Compared to that of the normal breast tissue, the RT and TTP seem faster (P<0.05), the PI and WIS seem higher in tumor tissues (P<0.05). Compared to that of the inside region of the tumor, TTP seem to be faster, PI and WIS seem higher in tumor periphery region (P<0.05). whereas blood perfusion parameters were no statistical differences in the2groups (≤2cm in diameter and>2cm in diameter)(P>0.05).3. Association of CEUS enhancement characteristics with prognostic factors. Heterogeneous enhancement was common in larger tumors (>2cm in diameter), and centripetal enhancement was common in negative ER expression. Penetrating vessel was found more often in the higher histologic grade and larger tumors. Perfusion defect was seen in negative ER expression, positive c-erb-B2expression, positive Ki-67expression and larger tumor diameter. The sensitivity, specificity and accuracy of perfusion defect for detection ER expression were86.7%,53.3%, and40%m, respectively. The sensitivity, specificity and accuracy of perfusion defect for detection Ki-67expression were78.2%,59.1%, and37.3%, respectively. The enhancement margin and enhancement shape showed no significant correlation with prognostic factors (P>0.05).4. Association of CEUS enhancement characteristics with MVD. Heterogeneous enhancement and perfusion defect were found more often in high-MVD group than in low-MVD group (P<0.05), whereas enhancement margin, enhancement shape and penetrating vessel showed no significant correlation with MVD (P>0.05). PI was higher in high-MVD group than that in low-MVD group (P<0.05), whereas the RT, TTP and WIS showed no significant correlation with MVD (P>0.05).Conclusions:1. CEUS not only evaluate the morphologic features of breast cancer, but also evaluate quantitatively the degree of blood perfusion.2. Some enhancement characteristics were associated with prognostic factors, which reflect in vivo the infiltration and metastasis of the tumor, and can be helpful to predict the breast caner prognosis.3. Some enhancement patterns and blood perfusion parameters were associated with MVD, which can be used as a quantitative basis for evaluation of tumor angiogenesis. Part2Potential application value of contrast-enhanced ultrasound in neoadjuvant chemotherapy of breast cancer Objective:Neoadjuvant chemotherapy (NAC) is the conventional treatment of choice for patients with locally advanced breast cancer. The reasonable application of NAC are pressing for a valuable tool to monitor and evaluate the response of breast cancer to neoadjuvant treatment. Although ultrasound (US) has applied to the efficacy evaluation of breast cancer, the accurate measurement of tumor sizes at US is still questioned all the time. The purpose of this study was to investigate the value of contrast-enhanced ultrasound (CEUS) in evaluating the response of breast cancer to NAC by assessing the tumor size changes and blood perfusion changes at CEUS before and after NAC.Methods:Thirty-one breast cancer patients treated with NAC (from2010.10until2012.02) and ultimately underwent surgery included. All patients were diagnosed with infiltrating ductal carcinoma (stage Ⅱ and Ⅲ) on the basis of results from a percutaneous core needle biopsy. The pre-therapy tumor size (at its longest dimension) was an average of (43±19) mm, ranging from22to108mm. Color Doppler Ultrasound Philips iU22(Philips, Bothell WA, USA) with Philips L9-3and L5-1probes were used in this examination. US was used to determine the site and maximum size of the primary tumor. Color Doppler was used to assess the grade of vascularization. CEUS was used to observe the tumor size changes, enhancement intensity and blood perfusion parameter changes before and after NAC. US and CEUS were performed for the31patients before and after3cycles NAC. The chemotherapy regimen included60mg/m2EPI intravenously (i.v.) on day1and75mg/m2DOC via i.v. on day1; these doses were repeated every21days for a total of3cycles prior to surgery. After completion of chemotherapy, all patients underwent mastectomy.Results:1. Tumor size changes before and after NAC. After NAC,25patients (80.6%) achieved a PR,4patients (12.9%) maintained a SD state, and2patients (6.5%) showed a PD state. The tumor sizes measured by CEUS were larger than those measured by US, and had high correlation with surgical specimens, with r values of 0.976. The sizes measured by US were smaller than the size of surgical specimens (P <0.05).2. Tumor blood perfusion changes before and after NAC. After NAC, US revealed the grade of vascularization decreased from the grade of2-3to0-1in most of the case. By comparison, the CEUS images revealed the enhancement intensity decreased in28cases (90.3%), but increased in2cases (6.5%). For one case (3.2%) without contrast agent perfusion in CEUS imaging pre-therapy, heterogeneous perfusion was observed post-therapy, while the tumor size remained stable. CEUS provided a more sensitive detection of the tumor necrosis. CEUS showed local blood perfusion defect in26cases (83.9%) prior to NAC, and27cases (87.1%) after NAC. However, the US did not show any necrosis liquefied areas in all cases before and after NAC.3. CEUS time-intensity curve analysis observed changes in blood perfusion quantitatively before and after chemotherapy, whereas US could not. After NAC, time to peak increased, peak intensity decreased, and wash-in slope decreased, with statistical differences between the two groups (P<0.05). However, the differences in the rise time and mean transit time were not statistically significant between the two groups (P>0.05).Conclusions:1. As compared with US, CEUS not only offers a more accurate measurement of the tumor size, but also reveals local blood perfusion defect in the tumor, which is critical for evaluating of breast cancer response to NAC.2. CEUS permits evaluation of the degree of blood perfusion in tumors qualitatively and quantitatively before and after NAC. Since a change in the tumor blood perfusion occurs earlier than a change in tumor size, which represents an indicator of the tumor survival, CEUS may represent a valuable tool for evaluating the early response of breast cancer to NAC.