Since the 1990s, when sentinel lymph node biopsy was applied to the surgical staging of lymph node of breast cancer, the widely accepted tracer method has been dyeing and isotopic method. [17–19] Although isotopic method is acknowledged the most accurate, it is limited to a certain extent to be extensively applied, because of its high cost and potential radiological hazards. Even though the dyeing method is simple and low-cost, there are also many problems such as tattoo effect and allergic reaction. [20–21] For patient who accepted nipple-sparing mastectomy and immediate implant-based reconstruction, the periareolar coloration caused by the dye may increase the risk of nipple necrosis. [22] CEUS-guided sentinel lymph node biopsy has been reported for more than a decade, especially in the last five years, correlative researches have increased year by year. By using ultrasonic enhanced agent, simple operation similar to dyeing method, with the assistance of ultrasound professional doctor, clinical surgeon can accurately know the location of the sentinel lymph node before the surgery, and when combination with wire positioning, the operation of sentinel node biopsy will be easier, the damage caused by the exploration of SLN may further reduced.
Based on the results of several prior prospective studies, the detection rate of CEUS-localized SLN was more than 90%. Li et al.'s study, which included a total of 453 patients, with a detection rate of 98.23%. [10] Zhong et al.'s study, that included 126 patients, with a detection rate of 100%. [23] In our result, the detection rate of SLN is 96.3%, that is consistent with previous researches and not inferior to the isotope and dye. In addition, consistent with previous reports, [12–14] the average number of SLNs identified by CEUS in our study was 1.3, which was significantly smaller than that obtained by dyeing. This is mainly attributed to differences in molecular weight between the tracers. [6, 7] The smaller the tracer molecular weight and the longer the tracer duration, the more likely it is to enter the secondary lymphatic vessels, which may lead to the removal of more non-sentinel lymph nodes, potentially increasing the risk of postoperative complications. Previous studies, like B32 and ALMANAC, also suggested that although SLNB has significantly reduced the risk of upper limb complication compared with ALND, about 8%~41% of patients still have upper limb paresthesia and other complications. [24] Retrospective studies and meta-analyses have demonstrated that there is still a certain morbidity of upper limb complications after SLNB surgery, the most common is axillary pain, which torments more than 10 percent of patients. [25–27] The reason may be largely due to excessive exploration of SLN. Previous study has suggested that, in a small minority of patients, the SLN for the breast and upper limb may be at the same station. [28] The CEUS method may be able to find the real SLN more quickly and accurately, reduce the exploration of other secondary lymph nodes, and may further reduce the occurrence of upper limb complications. Nowadays, a number of RCT studies about omitting sentinel lymph node biopsy are currently under way,[29] but the persuasive results and conclusions still need a long time of follow-up to be obtained, which naturally cannot be an optional strategy in current clinical practice. Therefore, reducing the surgical trauma of sentinel lymph node biopsy while ensuring the accuracy of its diagnosis may be a more practical approach at this stage, like the CEUS method.
In this study, all preoperatively located CE-SLNs were dyed. However, previous reports have shown that a few SLNs identified by CEUS may not be dyed, [9, 30] which may be related to the lymphatic drainage pattern of patients. It has been reported that the lymphatic drainage pattern from mammary gland to axilla can be divided into four modes: a single primary lymphatic vessel corresponds to a single SLN, a single primary lymphatic vessel after branching corresponds to two or more SLNs, multiple primary lymphatic vessels correspond to multiple SLNs, and multiple primary lymphatic vessels when aggregated correspond to a single SLN. [13] The first two modes account for more than 80% of the total, and the third is the rarest. So, if CE-SLN is found undyed, the first lymph node corresponding to the dyed primary lymphatic vessel must be removed to minimize the false-negative rate.
In our study, Three-quarters of the patients who failed to identified CE-SLN were node metastatic. Further analysis of CEUS operating records found that, in all lymph node positive patients, 47.4% belongs to the secondary operation group, and patients of this group had a sentinel lymph node positive rate of 42.8%, which may be related to poor flow of lymphatic tubes in patients with lymph node metastasis. [31] That suggested, in the clinical practice, the success rate of SLNB can be well predicting by the CEUS method, and in patients with CEUS failure, double tracing may be necessary to increase the success rate. On the contrary, in the patients with successful SLN localization after once CEUS operation, most of them are node negative, or only a mild tumor burden in the SLN. By this method, the axillary state or lymph node load can be accurately predicted before surgery.
Compared with the single dye method, the operation time of CEUS-guided SLNB is significantly reduced. Furthermore, the operation time of the dye method in this study might be shortened because of the guidance of guide wire, and the operation time of the single dye method may be longer. This technology may be able to shorten the learning curve of surgeons and improve the accuracy of SLN exploration. [32] The results indicated the false negative rate of CE-SLN was 0%. Although these patients did not undergo further ALND, but at least six lymph nodes including all dyed nodes were removed, and previous studies have shown that the risk of false negative rate is very small when more than 5 lymph nodes are removed. [1, 2]
Our study also has some limitations. Firstly, 83.5% of patients was in early breast cancer with stage T1, and the application value of this method to patients with larger tumor diameters still needs to be further studied. This study only investigated the methodological feasibility, and the effect on long-term recurrence are still lacking data. Meanwhile, the impact of this method on upper limb function needs to be further evaluated, proving whether its security is indeed superior to the traditional methods. The intraoperative tracer in this study only used blue dye, which is not the best single tracer, nor can it avoid the tattoo effect and other defects. CEUS combined with isotope may better avoid the defects of dye, and can also be used to verify the results of this study. More clinical studies still needed to confirm these results.