Abstract
Background
Preoperative evaluation of sentinel lymph nodes is very important in breast cancer patients. This study aimed to explore factors affecting the result of preoperative percutaneous contrast-enhanced ultrasound for sentinel lymph nodes (SLN-CEUS) using Sonovue.
Methods
A total of 176 patients with breast cancer who underwent preoperative SLN-CEUS to trace axillary sentinel lymph nodes were included. The positive result of SLN-CEUS was defined as both lymphatic vessels and SLN visible. The negative result was defined as the visible lymphatic vessels but the SLNs invisible, and neither lymphatic vessel nor SLNs invisible. Clinical features, histopathology, ultrasound features and doses of contrast agents were analyzed between the positive and negative groups.
Results
The diagnostic sensitivity, specificity, and accuracy of SLN-CEUS were 81.5%, 90.7%, and 87.8% respectively. The false negative and false positive rates were 18.5% and 9.3%. Age, distance from the anterior edge of the mass to the body surface (DTS), tumor location, pathologies and lymph nodes metastasis were significantly correlated with the results of SLN-CEUS between the negative and positive groups (P=0.032, 0.035, 0.036, 0.047 and <0.001). Logistic regression showed that age, location, DTS, and lymph node metastasis were independent factors influencing negative SLN-CEUS.
Conclusions
In conclusion, independent factors affecting negative results of SLN-CEUS were lymph node metastasis, age, tumor location and DTS.
Keywords: Breast cancers, sentinel lymph nodes (SLNs), contrast-enhanced ultrasound (CEUS)
Introduction
The assessment of sentinel lymph nodes (SLNs) plays a critical role in the clinical management of breast cancer. However, conventional imaging techniques often suffer from low sensitivity and accuracy in detecting SLNs, making intraoperative identification and localization necessary in most cases. In 2004, Goldberg et al. reported a breakthrough in the visualization of peritumoral lymph nodes in a porcine melanoma model by using percutaneous injection of contrast agents. This marked the advent of percutaneous contrast-enhanced ultrasound for sentinel lymph node assessment (SLN-CEUS) (1). Since then, several studies have demonstrated the utility of contrast-enhanced ultrasound (CEUS) for visualizing SLNs in various cancers, including breast, vulvar, penile, and oral/oropharyngeal cancers (2-4).
In a notable animal study, Favril et al. compared the effectiveness of near-infrared fluorescence and CEUS for SLN detection by injecting contrast agents percutaneously into the axillary, groin, and popliteal areas of dogs. Their findings highlighted that SLN-CEUS significantly enhanced the ability to detect axillary SLNs in real-time, offering a non-invasive, safe, and effective diagnostic tool (5-7). This technique is especially beneficial for early-stage breast cancer patients with clinically non-palpable axillary lymph nodes, as it may help avoid extensive axillary lymph node dissection (ALND) when combined with ultrasound-guided fine-needle or core needle biopsy (8,9).
Despite the growth of research on SLN-CEUS, the lack of a standardized technical protocol has limited its adoption as a routine preoperative examination in clinical settings, particularly in China (10). While the clinical value of SLN-CEUS has been widely reported, fewer studies have investigated the variables that influence its diagnostic outcomes. Studies have shown that transdermal injection of ultrasound contrast agents can result in significant variability in SLN-CEUS visualization rates (8,10-12). Importantly, a non-visible SLN on CEUS does not always indicate metastasis, and visible SLNs are not always free of metastatic involvement. However, there is currently no literature exploring the specific factors that influence percutaneous SLN-CEUS results, and false positives or negatives in SLN-CEUS findings require further investigation.
Therefore, this study seeks to evaluate the factors affecting the diagnostic performance of preoperative percutaneous SLN-CEUS using Sonovue (Bracco, Milan, Italy) in patients with breast cancer. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2879/rc).
Methods
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study involved human participants and was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiaotong University (No. 1.0/2017-3-30). Informed consent was taken from all individual participants.
Patients
A total of 176 consecutive patients, all diagnosed with breast cancer between February 2017 and February 2020, were included in this study. Each patient provided informed consent prior to undergoing SLN-CEUS. The inclusion criteria were as follows: (I) age over 18 years; (II) pathologically proved breast cancers with clinically non-palpable axillary lymph nodes; (III) voluntarily accepted SLN-CEUS procedure. Patients were excluded if they met any of the following conditions: (I) previous surgeries involving the affected breast or axilla; (II) severe cardiopulmonary or neurological disorders; (III) allergies to Sonovue; (IV) lost to follow-up. Four patients were excluded due to missing surgical pathology results, which made it impossible to verify the clinical stage of their tumors. Ultimately, 172 breast cancer patients with surgically confirmed axillary lymph node pathology were enrolled, with an average age of 53.1±11.0 years (range, 27–78 years).
Breast and axillary ultrasound examination
Patient information, including age, body mass index (BMI), and surgical history, was collected. Three radiologists, with 5, 10, and over 20 years of experience in breast ultrasound, were involved in this study. The Resona 7 ultrasound machine (Mindray Medical International, Shenzhen, China) was used for imaging and CEUS. For general breast and axillary ultrasound, a L14-5 probe with high frequency and image quality was employed, while the L11-3 probe was used for CEUS. All images were recorded, stored on a hard drive, and archived in the Digital Imaging and Communications in Medicine (DICOM) system. Key measurements, such as the distance from the anterior edge of the mass to the body surface (DTS), were taken. Lesions with three or more visible blood vessels on Doppler imaging were considered to have a rich blood supply. Bilateral axillary regions were scanned, and the size, location, and other ultrasound characteristics of suspicious lymph nodes were documented.
Percutaneous SLN-CEUS procedure
The ultrasound contrast agent Sonovue, consisting of sulfur hexafluoride microbubbles, was prepared by dissolving 59 mg of dry powder in 5 mL of saline. Using a 1 mL ortho Tuberculin syringe (OT) needle attached to a 5 mL syringe, 4.8 mL of the solution was extracted for injection. After disinfecting the areola area, one radiologist administered intradermal injections at four points of the periareolar region of the breast (positions corresponding to 3, 12, 9, and 6 o’clock on the left breast, 9, 12, 3, and 6 o’clock on the right). Gentle massage was performed after each injection to enhance lymphatic drainage. Simultaneously, another radiologist operated the ultrasound machine, performing CEUS in real-time with a low mechanical index (0.071–0.078). A dynamic scanning that continuous axial sweeping from the injection site to the axilla was performed. By tracing microbubble migration through lymphatic channels, and the “first-arriving” SLN was captured. The procedure was halted once the lymphatic vessels and nodes were clearly visible (Figure 1). Intradermal injection at the periareolar region mimics the lymphatic drainage patterns of similar to the standard blue dye or radioisotope technique before breast cancer surgery. This approach selectively enhances the axillary SLN while minimizing background parenchymal enhancement that may occur with intravenous injection. Key parameters, such as the number of injection sites, dose of Sonovue, number and diameter of visible lymphatic vessels, and the number and size of lymph nodes were recorded.
Figure 1.
Positive case of contrast enhanced ultrasound for sentinel lymph nodes, showing completed lymphatic and a small benign sentinel axillary lymph node.
A positive SLN-CEUS result was defined by the clear visualization of both lymphatic vessels and SLNs (Figure 2). A negative result occurred when lymphatic vessels were visible but SLNs were not, or neither vessels nor nodes could be detected (Figures 3,4). The location and number of SLNs were determined by tracing the visible lymphatic vessels. Lymph nodes with the presence of perfusion defect or heterogeneous perfusion on SLN-CEUS were defined as suspicious of metastasis (Figure 5). For suspicious of metastatic SLN-CEUS results, the lymphatic vessels and sentinel nodes were marked on the skin surface. For negative results, no markings were made. To ensure adequate time for microbubble accumulation in secondary lymph nodes (if present) and differentiation between true perfusion defects and technical artifacts, each CEUS session lasted at least 3 minutes, after which the contrast agent was allowed to clear and the skin puncture site disinfected. In cases where suspicious lymph nodes were detected, fine-needle aspiration (FNA) cytology was suggested and performed under ultrasound guidance.
Figure 2.
Positive case of contrast enhanced ultrasound for sentinel lymph nodes: female, 47 years old, tumor location was 10 o’clock in the left breast, size 20.3 mm × 17.7 mm × 13.6 mm, SLN-CEUS showed two lymph nodes in the left axillar. One is the sentinel lymph node (single arrows) and another one is the next stage that appeared later (double arrows). Pathology proved no lymph nodes metastasis after surgery. SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Figure 3.
Negative case of contrast enhanced ultrasound for sentinel lymph nodes: female, 56 years old, tumor location was 10–11 o’clock in the right breast, size 25.0 mm × 13.9 mm × 19.1 mm. An oval lymph node in the left axillar was shown in grey scale ultrasound, but SLN-CEUS visualized no lymph nodes (thin arrows). Only one lymphatic vessel (thick arrow) was traced from areolar region to the axillar. Pathology proved 16 lymph nodes metastasis after surgery. SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Figure 4.
Negative case of contrast enhanced ultrasound for sentinel lymph nodes: female, 63 years old, tumor location was 2 o’clock in the left breast, size 33.6 mm × 25.4 mm × 22.6 mm, SLN-CEUS visualized no lymphatic vessels and lymph nodes in the left axillar. Only one lymphatic vessel (double arrow) that in the anterior of mass (single arrow). Pathology proved no lymph nodes metastasis after surgery. SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Figure 5.
Negative case of contrast enhanced ultrasound for sentinel lymph nodes: metastasis lymph node with the presence of perfusion defect and peripheral lymphatic enhancement (thick arrows) on SLN-CEUS. SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Surgical procedure
Each patient’s treatment plan was formulated based on the results of core needle biopsies and a comprehensive clinical evaluation. The interval between SLN-CEUS and surgery ranged from 1 to 7 days. Patients classified as clinical stage III or higher received neoadjuvant chemotherapy. Those with confirmed preoperative axillary lymph node metastasis by FNA and up to 2 suspicious nodes on sonographies underwent modified radical mastectomy and ALND. While those with less than 3 suspicious nodes preoperatively, underwent modified radical mastectomy and intraoperative sentinel lymph node biopsy (SLNB). Patients without preoperational axillary metastasis evidence were treated with either mastectomy or breast-conserving surgery, followed by intraoperative SLNB. Final pathology reports confirmed the cancer type, presence of vascular tumor thrombus, and lymph node involvement. The final results of lymph node metastasis were confirmed by postoperative pathology of axillary lymph nodes. If no chances of surgeries, the pathological results of lymph nodes were obtained from FNA.
Statistical analysis
Clinical data, including patient demographics (age, BMI), tumor characteristics (DTS, tumor position, and maximum diameter), blood supply of the tumor, dose of contrast agents used, imaging outcomes, surgical methods, and histopathological findings (tumor type and presence or absence of vascular tumor thrombus), were meticulously recorded using Microsoft Excel. Statistical analysis was conducted using SPSS version 26.0 to evaluate the associations between these parameters and the imaging results. The diagnostic values of SLN-CEUS were determined by pathology results. True positive diagnosis was defined as suspicious of metastatic SLN-CEUS results and pathology proved metastatic axillary lymph nodes. True negative diagnosis was defined as both SLN-CEUS of no metastasis and pathologically proven benign axillary lymph nodes. False negative diagnosis was defined as positive SLN-CEUS (showing completed visible lymphatic and no perfusion defects of SLN) and pathologically proved metastatic axillary lymph nodes. While false positive diagnosis was defined as suspicious of metastatic SLN-CEUS results and pathology proved benign axillary lymph nodes. The diagnostic efficacy of SLN-CEUS and conventional ultrasonography (US) were calculated and compared.
The distribution of each clinical parameter was compared between the groups with positive and negative imaging outcomes. Categorical variables such as age (≥50 vs. <50 years), maximum tumor diameter (≥50 vs. <50 mm), tumor location (lateral and central regions vs. upper outer quadrant), blood supply of the tumor (rich vs. poor), and the presence of vascular tumor emboli were assessed using univariate Pearson’s Chi-squared analysis.
For continuous variables, a normality test was performed to determine the appropriate statistical method. Normally distributed variables, including DTS and dose of Sonovue, were compared between the positive and negative imaging groups using independent-sample t-tests. For non-normally distributed variables such as BMI, comparisons were made using the Mann-Whitney U test. Finally, binary logistic regression analysis was applied to identify independent factors influencing SLN-CEUS visualization.
Results
Clinical information
Among the 172 breast cancer patients included in this study, 48 underwent modified radical mastectomy, while 44 opted for breast-conserving surgery combined with intraoperative SLNB. In 14 patients, SLNB followed modified radical mastectomy, while the remaining 66 patients underwent both modified radical mastectomy and ALND. Pathological examination revealed 152 cases of invasive carcinoma, which included 142 invasive ductal carcinomas, 1 invasive lobular carcinoma, 6 cases of invasive ductal carcinoma combined with papillary carcinoma, 2 cases of invasive carcinoma with mucinous features, and 1 case of medullary carcinoma (Table 1). Additionally, 33 patients were diagnosed with vascular tumor emboli. Of the non-invasive cases, there were 20 instances, comprising 18 cases of ductal carcinoma in situ and 2 cases of lobular carcinoma in situ. Axillary lymph node metastasis was confirmed in 54 patients, while 118 had no evidence of axillary involvement.
Table 1. General information of sentinel lymph nodes contrast-enhanced ultrasound.
| Characteristic | Value |
|---|---|
| Age (years) | 53.1±11.0 [27–78] |
| Maximum diameter of tumor (mm) | 25.6±8.8 [6.6–63] |
| Cases of axillary lymph node metastasis | 54/172 (31.4) |
| Surgery | |
| Modified radical mastectomy with axillary lymph node dissection | 48/172 (27.9) |
| Breast-conserving surgery with axillary SLN biopsy | 44/172 (25.6) |
| Breast resection with axillary SLN biopsy | 14/172 (8.1) |
| Breast resections and axillary lymph node dissection | 66/172 (38.4) |
| Pathology | |
| Invasive ductal carcinoma | 142/172 (82.6) |
| Invasive lobular carcinoma | 1/172 (0.6) |
| Invasive ductal carcinoma with papillary carcinoma | 6/172 (3.5) |
| Invasive carcinoma with mucinous carcinoma | 2/172 (1.2) |
| Invasive carcinoma with medullary carcinoma | 1/172 (0.6) |
| Intraductal carcinoma in situ | 18/172 (10.5) |
| Lobular carcinoma in situ | 2/172 (1.2) |
| Suspicious of metastasis of SLN by SLN-CEUS | 55/172 (32.0) |
| ≥3 | 25/172 (14.5) |
| <3 | 30/172 (17.4) |
| FNA of suspicious SLN-CEUS | 48/55 (87.3) |
| SLN-CEUS positive (no suspicious LN) | 117/172 (68.0) |
| Pathology proved metastasis of SLN | 54/172 (31.4) |
Data are presented as mean ± standard deviation [range] or n/N (%). FNA, fine-needle aspiration; LN, lymph node; SLN, sentinel lymph node; SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Percutaneous SLN-CEUS and influencing factors
None of the patients experienced complications such as skin erosion or allergic reactions following the SLN-CEUS procedure. The mean dose of injected contrast agent was 0.76±0.53 mL, with a median dose of 0.6 mL and a range between 0.4 to 1.1 mL. Successful visualization of both lymphatic vessels and SLNs was achieved in 144 patients (83.7%), while in 28 cases (16.3%), SLNs were not visible. Among these negative cases, 14 exhibited lymphatic vessels but no detectable SLNs, 10 displayed only one lymphatic vessel, and 4 showed multiple lymphatic vessels without SLN visualization. Fifty-five cases of suspicious SLN diagnosed by SLN-CEUS. Among these patients, 48 cases accepted followed ultrasound guided FNA (Table 1).
Post-surgical pathological results revealed 45 true positive cases and 10 false positives following SLN-CEUS. There were also 107 true negatives and 11 false negatives. The diagnostic sensitivity, specificity, and accuracy of SLN-CEUS compared to conventional ultrasound were significantly superior: 83.3% vs. 63.0%, 91.5% vs. 58.5%, and 74.5% vs. 59.9%, respectively. Similarly, the positive predictive value (81.8% vs. 41.0%), negative predictive value (92.3% vs. 77.5%), false-negative rate (16.7% vs. 37.0%), and false-positive rate (8.5% vs. 9.3%) demonstrated the higher diagnostic efficacy of SLN-CEUS. A notable difference in the area under the curve (AUC) was observed between conventional ultrasound and SLN-CEUS in axillary lymph node diagnosis (0.607 vs. 0.861, P<0.001).
Percutaneous SLN-CEUS procedure was performed before the breast biopsy. The SLNs were successfully visible in all non-invasive breast cancers (20/20), while only 81.6% (124/152) were visible in invasive cancers, thus suggesting that all patients with non-invasive cancers had positive SLN-CEUS results, which was consistent with the optimal diagnosis. Univariate Chi-squared analysis showed that the pathological type of invasive carcinoma was significantly correlated with SLN-CEUS results (P=0.047, Fisher exact test). The ratio of lymph node metastasis was 66.7% in the negative group, while only 33.3% in the positive group. Lymph node metastases were significantly correlated with negative SLN-CEUS results (P<0.001).
Regarding tumor location, 37 cases were located in the upper inner quadrant, 10 in the lower inner quadrant, 27 in the lower outer quadrant, 83 in the upper outer quadrant, and 15 in the central region (nipple and areola). For statistical purposes, these locations were grouped into two categories: outer and central quadrants versus inner quadrants. SLN-CEUS results were positive in 80% of tumors in the outer and central regions and 93.6% in the inner quadrant, with a significant difference between the groups (P=0.036).
Independent-sample t-tests revealed no significant difference in BMI between the negative and positive SLN-CEUS groups (P=0.262). However, both age and distance to the skin (DTS) showed significant differences (P=0.032 and 0.035, respectively). The average tumor diameter was 25.6±8.8 mm, and the mean dose of Sonovue contrast agent used was 0.6 mL. The Mann-Whitney U test showed no significant differences in tumor size or contrast dose (P=0.104 and 0.824) (Table 2). Of the 130 tumors with abundant blood supply, there were no significant differences in size, morphology, blood supply, or the presence of tumor thrombus (P=0.104, >0.99, >0.99, and 0.068, respectively).
Table 2. Pearson Chi-squared analysis of factors affecting SLN-CEUS identification rate.
| Factors | SLN-CEUS | P value | ||
|---|---|---|---|---|
| Total (n=172) | Positive | Negative | ||
| Mass position | 0.036* | |||
| Outer and central quadrants | 125 (72.7) | 100 (80.0) | 25 (20.0) | |
| Inner quadrant | 47 (27.3) | 44 (93.6) | 3 (6.4) | |
| Morphology | >0.99* | |||
| Mass | 157 (91.3) | 26 (16.6) | 131 (83.4) | |
| No mass | 15 (8.7) | 2 (13.3) | 13 (86.7) | |
| Blood supply | >0.99 | |||
| Rich | 131 (76.2) | 110 (84.0) | 21 (16.0) | |
| Not rich | 41 (23.8) | 34 (82.9) | 7 (17.1) | |
| Histology type | 0.047* | |||
| Invasive cancer | 152 (88.4) | 124 (81.6) | 28 (100.0) | |
| Non-invasive cancer | 20 (11.6) | 20 (18.4) | 0 (0) | |
| Lymph node metastasis | <0.001 | |||
| Yes | 54 (31.4) | 36 (66.7) | 18 (33.3) | |
| No | 118 (68.6) | 108 (91.5) | 10 (8.5) | |
| Vascular tumor emboli | 0.068 | |||
| Yes | 33 (19.2) | 24 (72.7) | 9 (27.3) | |
| No | 139 (80.8) | 120 (86.3) | 19 (13.7) | |
| Dose of Sonovue (mL) | – | 0.6 (0.4–1.0) | 0.6 (0.4–1.1) | 0.824 |
| Maximum diameter (mm) | – | 23.5 (18.2–31.3) | 26.0 (21.0–35.6) | 0.104 |
| Age (years) | – | 52.4±11.1 | 56.9±9.5 | 0.032 |
| DTS (mm) | – | 6.6±3.1 | 5.28±2.8 | 0.035 |
| BMI (kg/m2) | – | 22.9±3.0 | 23.6±3.4 | 0.262 |
The data are presented as n (%), median (range), or mean ± SD. *, Fisher exact test. BMI, body mass index; DTS, distance from the anterior edge of the mass to the body surface; SD, standard deviation; SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Binary logistic regression identified age, tumor location (outer and central quadrants), lymph node metastasis, and DTS as independent predictors of a negative SLN-CEUS result [P value was 0.017, 0.042, <0.001 and 0.033, respectively, with odds ratios (ORs) of 0.946, 3.970, 5.460, and 1.205]. The combined accuracy of these four parameters in predicting a negative SLN-CEUS outcome was 82.0% (Table 3).
Table 3. Logistic regression analysis of factors affecting SLN-CEUS negative results.
| Factors | B | SD | Wald | P value | OR | 95% CI | |
|---|---|---|---|---|---|---|---|
| Low | Upper | ||||||
| Age | −0.056 | 0.023 | 5.726 | 0.017 | 0.946 | 0.903 | 0.990 |
| Mass position | 0.042 | ||||||
| Outer and central | 1.378 | 0.679 | 4.122 | 3.970 | 1.049 | 15.028 | |
| Inner quadrants (reference) | 0.000 | 1.000 | |||||
| Lymph node metastasis | <0.001 | ||||||
| Yes | 1.697 | 0.469 | 13.072 | 5.460 | 2.175 | 13.701 | |
| No (reference) | 0.000 | 1.000 | |||||
| DTS | 0.186 | 0.087 | 4.548 | 0.033 | 1.205 | 1.015 | 1.430 |
| Constant | 2.385 | 1.321 | 3.263 | 0.071 | 10.864 | ||
CI, confidence interval; DTS, distance from the anterior edge of the mass to the body surface; OR, odds ratio; SD, standard deviation; SLN-CEUS, contrast enhanced ultrasound for sentinel lymph nodes.
Discussion
Preoperative evaluation of axillary sentinel lymph nodes in breast cancer has consistently posed a significant challenge for radiologists. Conventional ultrasound, despite its widespread use, exhibits notable limitations. Prior studies have reported false-negative rates for sentinel lymph node metastasis ranging from 15.0% to 64.3%, attributed to the absence of distinct ultrasound features in metastatic axillary lymph nodes and technical constraints (13-17). The primary issue lies in conventional ultrasound’s inability to differentiate local foci of metastasis or micrometastasis within the lymph nodes (9). Furthermore, the small size and deep anatomical location of sentinel lymph nodes contribute to ultrasound’s reduced diagnostic efficacy. For example, Hideo reported in a study of 582 cases of cT1–2N0M0 breast cancer, found that 19.1% of patients had metastatic sentinel lymph nodes. The size of these metastases ranged from 0.2 to 16 mm, with median and mean values of only 3 and 4 mm, respectively (18). In addition to the challenge of identifying such small metastases, accurately locating sentinel lymph nodes within the many of axillary nodes adds further complexity. Previous studies indicated that only 64% to 78% of preoperative lymph node biopsies performed under ultrasound guidance corresponded with intraoperative sentinel lymph node identification (19,20). Our study similarly found conventional ultrasound to have lower sensitivity and specificity when assessing axillary nodes.
The use of microbubble contrast agents through percutaneous injection has introduced a method for visualizing and localizing sentinel lymph nodes. Once subcutaneously injected, the contrast agent travels via lymphatic vessels, significantly enhancing the detection of sentinel lymph nodes compared to conventional ultrasound and intravenous CEUS. This technique has been shown to improve both the identification rate of sentinel lymph nodes and the sensitivity and accuracy of preoperative diagnosis (11,16,21-26). For instance, a clinical study by Cox, which included 555 cases, revealed that following SLN-CEUS localization, the likelihood of missing more than two sentinel lymph nodes during biopsy dropped to just 2% (27). However, a significant limitation of SLN-CEUS is the occasional failure to identify the sentinel lymph node, which contributes to reduced sensitivity (10). Previous studies reported that the sensitivity of SLN-CEUS combined with biopsy for diagnosing sentinel lymph nodes ranged from 61% to 97%, with false-negative rates between 6.6% and 39% (21,28-30). In our study, the diagnostic sensitivity of SLN-CEUS, combined with ultrasound-guided FNA, was 83.3%, while the false-negative rate was 16.7%, aligning with earlier research findings.
The lymphatic system of the breast is generally divided into two main pathways: the deep lymphatic vessels, which are connected to the blood vessels surrounding the breast lobules and parenchyma, and the superficial system, which connects to the nipple and skin via the lymphatic ducts (31). Tumor cells may spread to lymph nodes through either or both of these pathways, leading to lymph node involvement in different regions. Superficial lymphatic vessels tend to be easier to visualize, whereas deeper lymphatic pathways are more likely to be missed during ultrasound imaging. Additionally, some patients may have two distinct sets of sentinel lymphatic vessels draining into multiple sentinel lymph nodes, which can further complicate ultrasound diagnosis (32).
In this study, we examined the factors contributing to negative SLN-CEUS results. Our findings indicated that several clinical features including age, pathology confirmed lymph node metastasis, tumor location in the upper outer or central quadrant, and the distance from the tumor to the skin (DTS), were independent risk factors for negative SLN-CEUS outcomes. These four parameters were found to be both reliable and effective predictors of negative SLN-CEUS results. Tumors located in the upper outer quadrant or central breast regions were more likely to yield negative SLN-CEUS findings. Even in the absence of lymph node metastasis, tumors in close proximity to the axilla might exert pressure on surrounding lymphatic vessels, impeding the flow of the contrast agent into the lymphatic system, or restricting it to superficial lymphatic vessels near the injection site. In elderly patients, sagging skin with reduced elasticity may result in insufficient pressure during contrast injection, increasing the likelihood of a negative SLN-CEUS. Additionally, when tumors are located at a considerable distance from the skin surface, the mass may obstruct lymphatic return, further complicating contrast agent flow and contributing to negative results.
Sever et al. conducted some of the first clinical research on SLN-CEUS, and over time, the sensitivity of SLN-CEUS in identifying sentinel lymph nodes increased from 89% in 2009 to 97% in 2011 (21,28-30). A subsequent multicenter study showed that radiologists could achieve proficiency in the technique after completing training in over 25 SLN-CEUS cases (33). Based on our experience, the precision of contrast agent injection, along with the operator’s experience, are critical factors in ensuring the accuracy of SLN-CEUS. Proper training is therefore essential for those performing SLN-CEUS.
In addition to negative SLN-CEUS, false-positive SLN-CEUS results (SLN-CEUS diagnosis of metastasis/pathology of non-metastasis) were observed 10/172 cases (5.8%) in our cohort. These findings primarily resulted from reactive lymphadenopathy with chronic inflammation or fibrotic changes in some benign nodes, which may cause heterogeneous perfusion mimicking metastasis. The present study does have some limitations. Firstly, it was a single-center study with a relatively small sample size. Secondly, we did not account for the potential variability in contrast agent injection techniques between different operators, an aspect that warrants further investigation.
Conclusions
Percutaneous SLN-CEUS offers a substantial improvement in the preoperative evaluation of axillary sentinel lymph nodes in breast cancer patients. However, when SLN-CEUS yields negative results, additional factors beyond lymph node metastasis, such as patient age, tumor quadrant location, and tumor depth from the skin, should be carefully considered.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study involved human participants and was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiaotong University (No. 1.0/2017-3-30). Informed consent was taken from all individual participants.
Footnotes
Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2879/rc
Funding: This study was supported by the National Natural Science Foundation of China (No. 82071928) and the Program of Shanghai Academic/Technology Research Leader (No. 23XD1401300).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2879/coif). All authors report the funding from the National Natural Science Foundation of China (No. 82071928) and the Program of Shanghai Academic/Technology Research Leader (No. 23XD1401300). Y.D. is an employee of Shanghai Aitrox Technology Corporation Limited. The other authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2879/dss
References
- 1.Goldberg BB, Merton DA, Liu JB, Thakur M, Murphy GF, Needleman L, Tornes A, Forsberg F. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology 2004;230:727-34. 10.1148/radiol.2303021440 [DOI] [PubMed] [Google Scholar]
- 2.Lahtinen O, Eloranta M, Anttila M, Kärkkäinen H, Sironen R, Vanninen R, Rautiainen S. Preoperative sentinel lymph node localization in vulvar cancer: preliminary experience with inguinal intradermal contrast-enhanced ultrasound. Eur Radiol 2018;28:2089-95. 10.1007/s00330-017-5155-7 [DOI] [PubMed] [Google Scholar]
- 3.Wakisaka N, Endo K, Kitazawa T, Shimode Y, Kato K, Moriyama-Kita M, Koda W, Ikeda H, Ishikawa K, Ueno T, Nakanishi Y, Kondo S, Sugimoto H, Yoshimura K, Tsuji H, Kawashiri S, Omoto K, Yoshizaki T. Detection of sentinel lymph node using contrast-enhanced agent, Sonazoid(™), and evaluation of its metastasis with superb microvascular imaging in oral and oropharyngeal cancers: a preliminary clinical study. Acta Otolaryngol 2019;139:94-9. 10.1080/00016489.2018.1535193 [DOI] [PubMed] [Google Scholar]
- 4.Gkegkes ID, Iavazzo C. Advantages by using the intradermal microbubbles for sentinel lymph node detection in penile cancer. Hell J Nucl Med 2016;19:289. 10.1967/s0024499100414 [DOI] [PubMed] [Google Scholar]
- 5.Favril S, Stock E, Hernot S, Hesta M, Polis I, Vanderperren K, de Rooster H. Sentinel lymph node mapping by near-infrared fluorescence imaging and contrast-enhanced ultrasound in healthy dogs. Vet Comp Oncol 2019;17:89-98. 10.1111/vco.12449 [DOI] [PubMed] [Google Scholar]
- 6.Liu X, Wang M, Wang Q, Zhang H. Diagnostic value of contrast-enhanced ultrasound for sentinel lymph node metastasis in breast cancer: an updated meta-analysis. Breast Cancer Res Treat 2023;202:221-31. 10.1007/s10549-023-07063-2 [DOI] [PubMed] [Google Scholar]
- 7.Machado P, Liu JB, Needleman L, Lazar M, Willis AI, Brill K, Nazarian S, Berger A, Forsberg F. Sentinel Lymph Node Identification in Patients With Breast Cancer Using Lymphosonography. Ultrasound Med Biol 2023;49:616-25. 10.1016/j.ultrasmedbio.2022.10.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fan Y, Luo J, Lu Y, Huang C, Li M, Zhang Y, Shao N, Wang S, Zheng Y, Lin Y, Shan Z. The application of contrast-enhanced ultrasound for sentinel lymph node evaluation and mapping in breast cancer patients. Quant Imaging Med Surg 2023;13:4392-404. 10.21037/qims-22-901 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Huang C, Luo J, Shan Z, Zhen T, Li J, Ma Q, Wei L, Liang J, Xie X, Zheng Y. The value of the improved percutaneous and intravenous contrast-enhanced ultrasound diagnostic classification in sentinel lymph nodes of breast cancer. Quant Imaging Med Surg 2024;14:2391-404. 10.21037/qims-23-1210 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Barentsz MW, Verkooijen HM, Pijnappel RM, Fernandez MA, van Diest PJ, van der Pol CC, Witkamp AJ, Hobbelink MG, Sever AR, van den Bosch MA. Sentinel lymph node localization with contrast-enhanced ultrasound and an I-125 seed: an ideal prospective development study. Int J Surg 2015;14:1-6. 10.1016/j.ijsu.2014.12.019 [DOI] [PubMed] [Google Scholar]
- 11.Matsuzawa F, Einama T, Abe H, Suzuki T, Hamaguchi J, Kaga T, Sato M, Oomura M, Takata Y, Fujibe A, Takeda C, Tamura E, Taketomi A, Kyuno K. Accurate diagnosis of axillary lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid. Mol Clin Oncol 2015;3:299-302. 10.3892/mco.2014.483 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zhong J, Sun DS, Wei W, Liu X, Liu J, Wu X, Zhang Y, Luo H, Li Y. Contrast-Enhanced Ultrasound-Guided Fine-Needle Aspiration for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer. Ultrasound Med Biol 2018;44:1371-8. 10.1016/j.ultrasmedbio.2018.03.005 [DOI] [PubMed] [Google Scholar]
- 13.Nakamura R, Yamamoto N, Miyaki T, Itami M, Shina N, Ohtsuka M. Impact of sentinel lymph node biopsy by ultrasound-guided core needle biopsy for patients with suspicious node positive breast cancer. Breast Cancer 2018;25:86-93. 10.1007/s12282-017-0795-7 [DOI] [PubMed] [Google Scholar]
- 14.Rao R, Lilley L, Andrews V, Radford L, Ulissey M. Axillary staging by percutaneous biopsy: sensitivity of fine-needle aspiration versus core needle biopsy. Ann Surg Oncol 2009;16:1170-5. 10.1245/s10434-009-0421-9 [DOI] [PubMed] [Google Scholar]
- 15.Baruah BP, Goyal A, Young P, Douglas-Jones AG, Mansel RE. Axillary node staging by ultrasonography and fine-needle aspiration cytology in patients with breast cancer. Br J Surg 2010;97:680-3. 10.1002/bjs.6964 [DOI] [PubMed] [Google Scholar]
- 16.Gkegkes ID, Iavazzo C. Contrast Enhanced Ultrasound (CEU) Using Microbubbles for Sentinel Lymph Node Biopsy in Breast Cancer: a Systematic Review. Acta Chir Belg 2015;115:212-8. 10.1080/00015458.2015.11681099 [DOI] [PubMed] [Google Scholar]
- 17.Chang JM, Leung JWT, Moy L, Ha SM, Moon WK. Axillary Nodal Evaluation in Breast Cancer: State of the Art. Radiology 2020;295:500-15. 10.1148/radiol.2020192534 [DOI] [PubMed] [Google Scholar]
- 18.Shigematsu H, Nishina M, Yasui D, Hirata T, Ozaki S. Minimal prognostic significance of sentinel lymph node metastasis in patients with cT1-2 and cN0 breast cancer. World J Surg Oncol 2019;17:41. 10.1186/s12957-019-1585-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Britton PD, Goud A, Godward S, Barter S, Freeman A, Gaskarth M, Rajan P, Sinnatamby R, Slattery J, Provenzano E, O'Donovan M, Pinder S, Benson JR, Forouhi P, Wishart GC. Use of ultrasound-guided axillary node core biopsy in staging of early breast cancer. Eur Radiol 2009;19:561-9. 10.1007/s00330-008-1177-5 [DOI] [PubMed] [Google Scholar]
- 20.Usmani S, Ahmed N, Al Saleh N, abu Huda F, Amanguno HG, Amir T, al Kandari F. The clinical utility of combining pre-operative axillary ultrasonography and fine needle aspiration cytology with radionuclide guided sentinel lymph node biopsy in breast cancer patients with palpable axillary lymph nodes. Eur J Radiol 2015;84:2515-20. 10.1016/j.ejrad.2015.10.003 [DOI] [PubMed] [Google Scholar]
- 21.Sever AR, Mills P, Weeks J, Jones SE, Fish D, Jones PA, Mali W. Preoperative needle biopsy of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasound in patients with breast cancer. AJR Am J Roentgenol 2012;199:465-70. 10.2214/AJR.11.7702 [DOI] [PubMed] [Google Scholar]
- 22.Saidha NK, Aggarwal R, Sen A. Identification of Sentinel Lymph Nodes Using Contrast-Enhanced Ultrasound in Breast Cancer. Indian J Surg Oncol 2018;9:355-61. 10.1007/s13193-017-0646-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Nielsen Moody A, Bull J, Culpan AM, Munyombwe T, Sharma N, Whitaker M, Wolstenhulme S. Preoperative sentinel lymph node identification, biopsy and localisation using contrast enhanced ultrasound (CEUS) in patients with breast cancer: a systematic review and meta-analysis. Clin Radiol 2017;72:959-71. 10.1016/j.crad.2017.06.121 [DOI] [PubMed] [Google Scholar]
- 24.Buonomo OC, Materazzo M, Pellicciaro M, Iafrate G, Ielpo B, Rizza S, Pistolese CA, Perretta T, Meucci R, Longo B, Cervelli V, Vanni G. Contrast-enhanced Ultrasound Using Intradermal Microbubble Sulfur Hexafluoride for Identification of Sentinel Lymph Nodes During Breast Cancer Surgery: A Clinical Trial. Anticancer Res 2023;43:557-67. 10.21873/anticanres.16192 [DOI] [PubMed] [Google Scholar]
- 25.Zhao J, Zhang J, Zhu QL, Jiang YX, Sun Q, Zhou YD, Wang MQ, Meng ZL, Mao XX. The value of contrast-enhanced ultrasound for sentinel lymph node identification and characterisation in pre-operative breast cancer patients: A prospective study. Eur Radiol 2018;28:1654-61. 10.1007/s00330-017-5089-0 [DOI] [PubMed] [Google Scholar]
- 26.Omoto K, Futsuhara K, Watanabe T. Sentinel lymph node identification using contrast-enhanced ultrasound in breast cancer: review of the literature. J Med Ultrason (2001) 2024;51:581-5. 10.1007/s10396-023-01313-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Cox K, Weeks J, Mills P, Chalmers R, Devalia H, Fish D, Sever A. Contrast-Enhanced Ultrasound Biopsy of Sentinel Lymph Nodes in Patients with Breast Cancer: Implications for Axillary Metastases and Conservation. Ann Surg Oncol 2016;23:58-64. 10.1245/s10434-015-4606-0 [DOI] [PubMed] [Google Scholar]
- 28.Cox K, Sever A, Jones S, Weeks J, Mills P, Devalia H, Fish D, Jones P. Validation of a technique using microbubbles and contrast enhanced ultrasound (CEUS) to biopsy sentinel lymph nodes (SLN) in pre-operative breast cancer patients with a normal grey-scale axillary ultrasound. Eur J Surg Oncol 2013;39:760-5. 10.1016/j.ejso.2013.03.026 [DOI] [PubMed] [Google Scholar]
- 29.Sever AR, Mills P, Jones SE, Cox K, Weeks J, Fish D, Jones PA. Preoperative sentinel node identification with ultrasound using microbubbles in patients with breast cancer. AJR Am J Roentgenol 2011;196:251-6. 10.2214/AJR.10.4865 [DOI] [PubMed] [Google Scholar]
- 30.Sever A, Jones S, Cox K, Weeks J, Mills P, Jones P. Preoperative localization of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasonography in patients with breast cancer. Br J Surg 2009;96:1295-9. 10.1002/bjs.6725 [DOI] [PubMed] [Google Scholar]
- 31.Fowler JC, Solanki CK, Guenther I, Barber R, Miller F, Bobrow L, Ravichandran D, Lawrence D, Ballinger JR, Douglas-Jones A, Purushotham AD, Peters AM. A pilot study of dual-isotope lymphoscintigraphy for breast sentinel node biopsy comparing intradermal and intraparenchymal injection. Eur J Surg Oncol 2009;35:1041-7. 10.1016/j.ejso.2009.02.018 [DOI] [PubMed] [Google Scholar]
- 32.Shimazu K, Miyake T, Tanei T, Naoi Y, Shimoda M, Kagara N, Kim SJ, Noguchi S. Real-Time Visualization of Lymphatic Flow to Sentinel Lymph Nodes by Contrast-Enhanced Ultrasonography with Sonazoid in Patients with Breast Cancer. Ultrasound Med Biol 2019;45:2634-40. 10.1016/j.ultrasmedbio.2019.07.005 [DOI] [PubMed] [Google Scholar]
- 33.Li J, Li H, Guan L, Lu Y, Zhan W, Dong Y, et al. The value of preoperative sentinel lymph node contrast-enhanced ultrasound for breast cancer: a large, multicenter trial. BMC Cancer 2022;22:455. 10.1186/s12885-022-09551-y [DOI] [PMC free article] [PubMed] [Google Scholar]
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