Abstract
Objective: To explore the correlation between rim enhancement features of contrast-enhanced ultrasound and lymphatic metastasis, and to provide theoretical support for clinical treatment of breast cancer. Methods: 387 breast cancer patients (748 axillary lymph nodes in total) treated in our hospital from January 2017 to January 2020 were selected and analyzed by contrast-enhanced ultrasound. Pathological examination showed that 540 axillary lymph nodes showed metastasis whereas 208 axillary lymph nodes did not show metastasis. Univariate analysis and Logistic stepwise regression were used to analyze the correlation between rim enhancement features of contrast-enhanced ultrasound and axillary lymph node metastasis of breast cancer. Results: Peripheral halo, peripheral convergence, rim enhancement, enhancement mode, enhancement amplitude, enhancement sequence, expansion after enhancement, peak intensity, time to peak, area under curve, thrombolysis in myocardial infarction, perfusion sequence, aspect ratio, and maximum cortical thickness were all related to lymph node metastasis of breast cancer by univariate analysis, and the difference was statistically significant (P < 0.05). Multivariate analysis showed that enhancement mode, enhancement amplitude, extension after enhancement, maximum cortical thickness, peak intensity and time to peak were all related to lymph node metastasis of breast cancer. Conclusion: Rim enhancement features of contrast-enhanced ultrasound of breast cancer are related to lymph node metastasis, which will provide a guidance for clinical treatment of breast cancer.
Keywords: Breast cancer, contrast enhanced ultrasound, lymph node metastasis, relevance
Introduction
Breast cancer (BC) is a malignant tumor with the highest incidence among common female diseases, which seriously affects the physical and mental health and even endangers the lives of the patients [1-4]. According to relevant reports, the incidence of BC accounts for 7%-10% of malignant tumors, and it mostly occurs in middle-aged and elderly women [4,5]. However, in recent years, the incidence has increased year by year, and it gradually begins to affect the younger generation. Axillary lymph node is an important path of BC lymph node metastasis, which serves as a crucial basis in selecting treatments and evaluating prognosis in clinic [5-8]. Ultrasonic contrast is a highly accurate and non-invasive examination method, which can predict whether BC lymph node metastasis occurs according to imaging analysis. Based on this, in this study, the correlation between rim enhancement features of contrast-enhanced ultrasound (CEUS) and lymph node metastasis of BC was explored by analyzing the rim enhancement features of axillary lymph nodes of BC, so as to provide a reference for clinical treatment of BC.
Materials and methods
General data
387 patients with BC admitted to our hospital for treatment from January 2017 to January 2020 were selected. All the objects enrolled were female, aged from 31 to 76 years old, with an average age of (50.4 ± 3.5) years old, including 341 cases of invasive ductal carcinoma (IDC) and 46 cases of ductal carcinoma in situ (DCIS). All patients received the CEUS for BC before the operation, and 748 axillary lymph nodes were detected, all of which were ipsilateral lymph nodes of BC. After pathological study and diagnosis, 540 axillary lymph node metastases were set as lymph node metastasis group, while 208 axillary lymph nodes without metastasis were included in the lymph node non-metastatic group. There was no statistical difference in general data between the two groups of BC patients (P > 0.05), so they can be enrolled in this study.
Inclusion criteria
① Patients meet the clinical diagnostic criteria of BC; ② The patients have complete clinical medical records; ③ This study was approved by the hospital’s ethics committee. Patients and their families were informed of the purpose and process of this experimental study, and signed an informed consent.
Exclusion criteria
① Patients complicated with brain, heart, kidney, liver and other organ and tissue diseases; ② Patients with mental and other cognitive disorders or patients refusing to cooperate in the study; ③ Patients complicated with systemic coagulation disorder; ④ The clinical data of patients are incomplete.
Methods
Ultrasound diagnostic instrument (Philips iU22), L9-4 Broadband Linear Array Transducer and the contrast software were used with frequency probe of 9.0 MHz and contrast mechanical index of 0.08. Patients kept lying on their backs, with their arms raised and extended outward, exposing their armpits [9-11]. Multiple sections were scanned continuously, and the target lymph nodes were locked in several lymph nodes detected, and one or more clear and meaningful ones in the sonogram were taken for examination [12-14]. The largest long axis section of the lymph node was taken, the probe was kept stable and switched to the contrast mode [15-18]. The 2 ml contrast agent was quickly injected into the elbow vein, followed by injection of 5 ml normal saline, and the section remained unchanged, and the timer was started. The perfusion process of contrast agent was observed continuously for 90 s, and the dynamic whole process of CEUS was stored for subsequent analyses [19-21].
Image analysis
The following indexes were recorded, including BC focus, location, size, aspect ratio, shape, boundary, capsule, internal echo of the focus, internal calcification, peripheral acoustic halo, ratio of cortex to medulla (maximum thickness of cortex to thickness of upper medulla), maximum thickness of cortex, blood flow characteristics of lymph node, contrast perfusion sequence, enhancement features, whether the scope is enlarged after enhancement, whether the boundary is clear, peak intensity, time to peak, area under curve and blood flow signal in lymph nodes. Through semi-quantitative analysis of Alder classification, it can be divided into grade 0, I, II and III. The ultrasonic contrast-enhanced images of axillary lymph nodes were analyzed offline by professional doctors, and the diagnosis results were completed independently. If it is not consistent with the doctor’s diagnosis, re-reading the image until an agreement has been reached and then the image can be included in this study.
Statistical analyses
The data obtained in this study were statistically analyzed and processed by SPSS20.0 software. X2 test was carried out on the count data, expressed as [% (n)]. A t test was performed for measurement data, presented as (x ± s). P < 0.05 indicated statistically significant differences. Logistic stepwise regression was used to analyze multiple factors.
Results
Comparative analysis of general data of two groups of patients
Table 1 displays that the difference of general data between the two groups did not reach statistical significance.
Table 1.
Comparative analysis of general data of two groups of patients
| Lymph node non-metastasis group (n=208) | Lymph node metastasis group (n=540) | t or X2 | P | |
|---|---|---|---|---|
| Age (years old) | 49.1 ± 2.8 | 48.7 ± 3.4 | 1.1019 | 0.2712 |
| Education level | 1.7516 | 0.186 | ||
| Junior high school and below | 39 (18.75%) | 73 (13.52%) | ||
| High school and above | 169 (81.25%) | 467 (86.48%) | ||
| Anamnesis | 0.4597 | 0.498 | ||
| Hypertension | 25 (12.02%) | 41 (7.59%) | ||
| Diabetes | 22 (10.58%) | 63 (11.67%) | ||
| None | 161 (77.40%) | 436 (80.74%) | ||
| Smoking | 0.4365 | 0.509 | ||
| Yes | 17 (8.17%) | 33 (6.11%) | ||
| No | 191 (91.83%) | 507 (93.89%) | ||
| Alcohol drinking | 0.8293 | 0.362 | ||
| Yes | 63 (30.29%) | 139 (25.74%) | ||
| No | 145 (69.71%) | 401 (74.26%) | ||
| Residence | 0.2388 | 0.625 | ||
| Town | 132 (63.46%) | 328 (60.74%) | ||
| Countryside | 76 (36.54%) | 212 (39.26%) |
Univariate correlation analysis between rim enhancement features of CEUS and lymph node metastasis in BC
Correlation between rim enhancement features of CEUS and lymph node metastasis in BC
Whether the boundary is clear after enhancement has no statistical significance with lymph node metastasis of BC (P > 0.05). Lymph node non-metastasis group had 35 case peripheral halo, 29 case peripheral convergence, 162 case radial enhancement, 171 case homogeneous, 63 case high enhancement, 42 case centripetal, 38 case expanded scope after enhancement; while in the lymph node metastasis group, the number was 456, 123, 236, 69, 364, 427 and 423 respectively. The difference in peripheral halo, peripheral convergence, rim enhancement, enhancement mode, enhancement amplitude, enhancement sequence and expansion after enhancement between the two groups exhibited statistical significance with lymph node metastasis of BC (P < 0.05), see Table 2 for details.
Table 2.
Correlation between rim enhancement of CEUS and lymph node metastasis of BC
| Group | Lymph node non-metastasis group (n=208) | Lymph node metastasis group (n=540) | X2 | P |
|---|---|---|---|---|
| Peripheral halo | 311.9846 | 0.000 | ||
| Yes | 33 (15.87%) | 456 (84.44%) | ||
| No | 175 (84.13%) | 84 (15.56%) | ||
| Peripheral convergence | 7.2398 | 0.007 | ||
| Yes | 29 (13.94%) | 123 (22.78%) | ||
| No | 179 (86.06%) | 417 (77.22%) | ||
| Rim enhancement | 70.4652 | 0.000 | ||
| Radial enhancement | 162 (77.88%) | 236 (43.70%) | ||
| Non-radial enhancement | 46 (22.12%) | 304 (56.29%) | ||
| Enhancement mode | 322.2195 | 0.000 | ||
| Homogeneous | 171 (82.21%) | 69 (12.78%) | ||
| Nonhomegeneous | 37 (17.78%) | 471 (87.22%) | ||
| Enhancement amplitude | 64.5369 | 0.000 | ||
| High enhancement | 63 (30.29%) | 364 (67.41%) | ||
| Other enhancement | 135 (7.21%) | 176 (32.59%) | ||
| Enhancement sequence | 222.6093 | 0.000 | ||
| Centripetal | 42 (20.19%) | 427 (79.07%) | ||
| Non-centripetal | 166 (79.81%) | 113 (20.93%) | ||
| Enhanced boundary | 0.3981 | 0.528 | ||
| Clear | 97 (46.63%) | 238 (44.07%) | ||
| Unclear | 111 (53.37%) | 302 (55.93%) | ||
| Expanded scope after enhancement | 229.0899 | 0.000 | ||
| Yes | 38 (18.27%) | 423 (78.33%) | ||
| No | 170 (81.73%) | 117 (21.67%) |
Correlation analysis of peak intensity (PI), time to peak (TTP) and area under curve (AUC) with lymph node metastasis of BC
The PI, TTP and AUC of CEUS were significantly different from those of BC lymph node metastasis (P < 0.05), see Table 3 for details.
Table 3.
Analysis of PI, TTP and AUC of CEUS in two groups (x̅ ± s)
| Group | PI | TTP | AUC |
|---|---|---|---|
| Lymph node non-metastasis group (n=208) | 5.67 ± 3.79 | 28.41 ± 17.81 | 276.29 ± 183.71 |
| Lymph node metastasis group (n=540) | 9.02 ± 4.34 | 22.46 ± 16.05 | 368.38 ± 214.64 |
| t | 9.7866 | 4.4036 | 5.4642 |
| P | 0.000 | 0.000 | 0.000 |
Correlation analysis between other related indexes of CEUS and lymph node metastasis of BC
There was no significant difference between the ratio of internal perfusion defect and the ratio of cortex to medulla and lymph node metastasis of BC (P > 0.05). Thrombolysis in myocardial infarction (TIMI), perfusion sequence, aspect ratio and maximum cortical thickness were related to lymph node metastasis of BC (P < 0.05), see Table 4 for details.
Table 4.
Correlation analysis between other indexes of CEUS and lymph node metastasis of BC
| Group | Lymph node non-metastasis group (n=208) | Lymph node metastasis group (n=540) | X2 | P |
|---|---|---|---|---|
| TIMI | 302.4986 | 0.000 | ||
| 0-I | 41 (19.71%) | 465 (86.11%) | ||
| II-III | 167 (80.29%) | 75 (13.88%) | ||
| Perfusion sequence | 20.5730 | 0.000 | ||
| Hilar 30 on se | 84 (40.38%) | 128 (23.71%) | ||
| Cortex (%) n se | 124 (59.62%) | 412 (76.29%) | ||
| Internal perfusion defect | 1.2022 | 0.273 | ||
| Yes | 73 (35.09%) | 213 (39.44%) | ||
| No | 135 (64.91%) | 327 (60.56%) | ||
| Aspect ratio | 163.5407 | 0.000 | ||
| < 1.8 | 137 (65.87%) | 95 (17.59%) | ||
| ≥ 1.8 | 71 (34.13%) | 445 (82.41%) | ||
| Maximum cortical thickness | 85.7201 | 0.000 | ||
| ≤ 3 | 126 (60.58%) | 133 (24.63%) | ||
| > 3 | 82 (39.42%) | 407 (75.37%) | ||
| Ratio of cortex to medulla | 0.4326 | 0.511 | ||
| < 1 | 64 (30.77%) | 153 (28.33%) | ||
| ≥ 1 | 144 (69.23%) | 387 (71.67%) |
Logistic stepwise regression analysis
The dependent variable was lymph node metastasis of BC, and the independent variable was a statistically significant index in univariate analysis. Logistic stepwise regression analysis was performed, and the detailed data were shown in Table 5. The results showed that enhancement mode, enhancement amplitude, extension after enhancement, maximum cortical thickness, peak intensity and peak time were all related to lymph node metastasis of BC (P < 0.05).
Table 5.
Multivariate Logistic stepwise regression analysis of lymph node metastasis of BC
| Item | Β value | SE | X2 | OR (95% CL) | P |
|---|---|---|---|---|---|
| Enhancement mode (nonhomogeneous/homogeneous) | 1.025 | 0.317 | 22.824 | 3.805 (2.503-4.972) | < 0.001 |
| Expanded after enhancement (Yes/No) | 1.342 | 0.364 | 26.507 | 4.106 (2.845-5.746) | < 0.001 |
| Enhancement amplitude (High/other enhancements) | 1.160 | 0.328 | 5.133 | 3.868 (2.517-5.263) | 0.008 |
| Maximum cortical thickness (≤ 3 cm/> 3 cm) | 0.948 | 0.315 | 14.262 | 3.154 (2.208-4.525) | < 0.001 |
| Peak intensity (High/low) | 0.704 | 0.258 | 3.925 | 2.117 (1.805-3.214) | 0.026 |
| Time to peak (Long/short) | 0.437 | 0.116 | 4.208 | 1.824 (1.526-2.860) | 0.017 |
Analysis of CEUS features of BC lymph nodes
Female, 45 years old, lymph node metastasis in breast cancer. CEUS shows that the outline of lymphadenography increases significantly and nonhomogeneous enhancement. CEUS shows the cortex becomes thicker when lymph node metastasis occurs, with the maximum thickness exceeding 3 mm. The analysis of CEUS features of BC lymph nodes in this study was shown in Figure 1.
Figure 1.
CEUS of BC lymph nodes. Note: (A) Shows that the outline of lymphadenography increases significantly and nonhomogeneous enhancement. (B) Shows that the cortex becomes thicker when lymph node metastasis occurs, with the maximum thickness exceeding 3 mm.
Discussion
In recent years, the incidence of BC is increasing year by year, which seriously threatens the quality of life and health of women. Lymph node metastasis aggravates BC and is an important indicator for its efficiency of clinical treatment. Doctors are required to make a diagnosis after accurately evaluation of the lymph node metastasis status of BC, and choose the appropriate treatment and prognosis evaluation scheme correspondingly [22,23]. CEUS is characterized by high accuracy and non-invasion in the examination of BC, which can display the size of the tumor and the shape of the surrounding neovascularization in real time and in a dynamical manner, while the rim enhancement features of CEUS can improve the resolution of contrast-enhanced images, thereby enhancing the accuracy of BC diagnosis [24].
According to this study, peripheral halo, peripheral convergence, rim enhancement, enhancement mode, enhancement amplitude, enhancement sequence, expansion after enhancement, PI, TTP, AUC, TIMI, perfusion sequence, aspect ratio and maximum cortical thickness were all related to lymph node metastasis of BC by univariate analysis. Multivariate analysis showed that enhancement mode, enhancement amplitude, extension after enhancement, maximum cortical thickness, PI and TTP were all related to lymph node metastasis of BC. From this result, it can be concluded that when doctors perform CEUS examination on patients, the scope expands after enhancement, which indicates the possibility of metastasis of BC lymph nodes. The lymph nodes of metastatic BC are usually nonhomogeneously enhanced, and most of them were accompanied with internal defects, which was largely due to the metastasis of the tumor through the new tiny lymphatic vessels or microvessels around the lymph nodes. The internal defect should be attributed to the fact that the tumor cells directly destroyed or blocked the internal vascular network, resulting in local ischemic necrosis of the internal vascular network. The conclusion of this study was consistent with previous study [25], which supported a correlation between the enhancement mode of BC lymph nodes and axillary lymph node metastasis, while CEUS technology can accurately detect and diagnose BC lymph node metastasis. The metastatic lymph nodes are mainly high enhancement, usually showing marginal or intermediate defects”. This conclusion fully proves that the enhanced features of CEUS in BC are related to lymph node metastasis. The limitation of this study is that it did not calculate the sensitivity and specificity of the edge enhancement feature of BC in the diagnosis of lymph node metastasis, and its effectiveness will be further explored in future trials.
To sum up, the rim enhancement features of CEUS have a certain correlation with lymph node metastasis of BC, which can accurately evaluate the growth of microvessels around lymph nodes, provide theoretical basis in the selection of appropriate treatments, with a great value for clinical treatment of BC.
Disclosure of conflict of interest
None.
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