The present prospective study reports a radioisotope-free method of SLNB using a combination of ICG and MB that had a 99.6% detection rate. After a median follow-up of 5.6 years, the ipsilateral axillary recurrence rate in patients with negative SLNs was 0.64% and the incidence of upper extremity arm lymphedema was 2.1%. The dual tracing modality of ICG and MB, without radioactive isotopes, was an effective method for SLNB in patients with early breast cancer.
Although blue dye has no radiation exposure and is not expensive, its injections may cause skin necrosis and anaphylaxis , which was absent when ICG was used. The approach of blue dye was cheap but achieved lower identification rate. Both RI and ICG could increase the detection rate but need additional apparatus which means increased cost [8, 9]. Previous studies have compared the cost of RI and ICG, which showed $331 – $420 per patient for RI and $5 - $111 per patient for ICG , and it cost $18 per patient in China similarly. It seemed a little bit cheaper for ICG than RI, however, we could not conclude ICG is more cost-effective than RI. Based on our practical experience, the use of ICG made the surgical operation more visualized, it’s easier and quicker for us to find the SLN. But we did not have accurate records of the surgery time. Other study have reported that the average time between skin incision and SLN identification was 7 ± 6 min when using ICG . And it has been showed in a randomized controlled trial that the time to detect the first SLN was similar between multimodal method (combination of RI, ICG and blue dye) and RI alone (6.5 ± 5.16 vs. 8.0 ± 4.35 min; p = 0.13) .
The fluorescent ICG tracer helps to visualize lymphatic drainage from breast to axilla for incision localization and SLN identification, and, as in our study, previous trials have shown detection rates as high as 99 percent [22, 23]. Although age, BMI, tumor location, and excisional biopsy have all been reported to associate with decreased SLN detection rates [24–27], we achieved very high sensitivity in our study independent of negative factors when ICG and MB were used together.
FNR is a crucial indicator for assessing the accuracy of SLNB. However, FNR was not analyzed in our study. Since MB was already considered a reliable tracer method in China , and no additional ALND was performed in patients with negative SLNs, calculating the FNR of ICG and MB would have been difficult.
Instead, the efficacy of SLNB traced by combination of ICG and MB was evaluated in terms of long term ipsilateral axillary recurrence. Although previous studies have examined the rate of ipsilateral axillary recurrence after SLNB with ICG tracer, they have enrolled relatively few patients and the time of follow-up was short [28, 29]. In our study, after a median follow-up of 5.6 years, the ipsilateral axillary recurrence rate of was 0.64%, which was comparable to the result reported in the NSABP B32 trial and previous studies using different tracers (Table 3) [28–32].
Ipsilateral axillary recurrence rates
Patients with SLNB alone
Axillary recurrence rate
Krag et al
RI + blue dye
Inoue et al
ICG + blue dye
Boniface et al
RI + blue dye
Galimberti et al
Toh et al
ICG + blue dye
|SLNB, Sentinel lymph node biopsy; RI, Radioisotope; ICG, Indocyanine green.|
The number of SLNs that should be excised for accurate lymph node staging is controversial. Is detection of relatively more SLNs helpful in accurate axillary staging? And how many SLNs are enough? Several studies suggested that SLNB should not remove only one or two lymph node(s) when other labeled nodes are present, and in cases where 4 or more SLNs were removed accuracy reached 100% and the FNR dropped to zero [33, 34]. In patients undergoing SLNB after neoadjuvant chemotherapy, a dual tracer reached an acceptable FNR when more than 2 SLNs were detected . In our study, the median number of SLNs detected by the combined method was 3, a little bit higher than traditional methods. It was reported that more SLNs identified by ICG was probably due to the low molecular weight and high degree of diffusion of ICG allowing it to spread beyond the SLN to secondary draining lymph node . ICG could bind rapidly and completely to proteins. After intradermal or subcutaneous injection, ICG could theoretically bind to proteins and consequently became larger molecular tracer . And it has been shown in a double-blind randomized trial that the average number of detected SLNs by ICG or ICG:HSA (adsorption of ICG to human serum albumin) were not significantly different . We think the more reasonable explanation for a little bit more SLNs was due to the higher sensitivity of ICG method. It does not rely on visual search for dye but on light of fluorescence. Fluorescence can penetrate through thin layers of tissue and reveal nodes otherwise hidden when using MB . We believe that the dual tracer with ICG and MB would be useful in SLNB, even after neoadjuvant chemotherapy. Further studies will be needed.
Our study showed that the detection rate of positive lymph nodes was 69.3% by MB alone. More positive lymph nodes could be detected by dual tracers. However, it was comparable with the results of NSABP B32 study. The detection rate of positive lymph nodes was 77.5% and 93% by blue dye and combined method, respectively . The number of positive lymph nodes at SLNB is very important for subsequent decision making. Patients undergoing breast-conserving surgery with only 1 or 2 positive SLNs who meet the entry criteria for the ACOSOG Z0011 trial can be exempted from ALND . In our study, among 28 patients with more than 2 positive SLNs detected by the dual tracer, 67.9% had only 2 or less positive SLNs detected by MB alone. Therefore, the application of ICG could be helpful in accurate decision making with a higher number of positive SLNs.
Some may argue that excision of more SLNs detected by ICG will increase the incidence of lymphedema. The present study is the first one to report the incidence of lymphedema after SLNB with ICG tracer in a large sample cohort. The incidence of breast cancer treatment-related lymphedema following SLNB was 2.1%, whereas that following ALND was 14%. Goldberg reported on a series of 600 patients received SLNB by combined dye-isotope mapping technique, the incidence of patient-reported lymphedema was 3% . And another report showed that the incidence of subjective lymphedema after SLNB was 4.1% . Therefore, from the results of our study, it seems that SLNB with a dual tracer of combined ICG and MB is not related to an increased risk of lymphedema.
Our study has some shortcomings. RI has not been available in the majority of the hospitals in China, and it is regrettable we did not compare the dual ICG and MB tracer with the standard method of RI and blue dye recommended by the guidelines. We have also noticed that several studies compared the combination of ICG and RI to RI and blue dye . with the purpose of replacing blue dye with ICG in the dual tracer method. Clearly, this was not our goal. Since previous studies have shown that ICG performed similarly to RI with regard to the number of SLNs identified, rate of failed mapping, and identification of pathologically positive SLNs [41, 42], the hypothesis of replacing RI by ICG in a dual tracer method was reasonable.