This prospective and self-matching study aimed to compare LFIS with conventional NIR system and blue dye method to assess whether the former can be used as a reliable alternative and whether it is superior over blue dye method for early breast cancer.
ICG has a short half-life in plasma. After injection, it can bind tightly to plasma proteins and immediately enter lymphatic vessels to flow to SLNs [13]. Thus, ICG serves as a marker for a specific molecule or cell. SLNs in breast cancer regularly occur in specific areas. Thus, the precise location of incision can be readily chosen, and SLNs are easy to find under fluorescence guidance. The NIR fluorescence band of ICG is 700–900 nm, which is invisible to the naked eye. Therefore, the position and movement of these molecules and cells must be assisted by a NIR fluorescence imaging system to obtain the accurate location of lymphatic vessels and sentinel lymph nodes. Although the ICG fluorescence method is unique in surgical navigation and has high sensitivity, its application to current NIR systems encounters several technical issues that must be addressed. The current NIR system displays the fluorescence image on the mobile monitor, and the surgeon must alternately and repeatedly look at the surgical field and the remote monitor to confirm the site of the lymph nodes. This phenomenon destroys the consistency and increases the complexity of the surgical procedure. A Google-enhanced imaging system was developed in collaboration with the University of Science and Technology of China. When the surgeon wears Google Glasses, the fluorescent signal is projected onto the Google Glasses to achieve real-time display of approximate surgical field [14, 15]. This study presents a novel NIR system called LFIS that can continuously and accurately project the fluorescence image on the surgical field to allow for a focused vision and shorten the operation time. The LFIS provides real-time navigation for SLNB and has two modes: projection mode and lighting mode, which shifts by pressing one button, thus limiting the need to switch the shadowless lamp. LFIS is comparable to conventional NIR systems in locating sentinel nodes. Owing to self-matching, quantitative comparison under short surgery duration is unavailable.
The detection rate of LFIS-guided ICG combined with MB (100%, 184/184) was better than that of MB alone (86.96% (160/184), and this finding was consistent with previous studies. The total number of LFIS positive (176) was higher than that of MB positive (160) and is possibly related to the affinity for the lymphatic system. The affinity of ICG is stronger than that of MB because of the molecular structure and diameter; the molecular mass of ICG (774.9) is larger than that of MB (319.9) [16].
ICG fluorescence imaging has been favored by researchers as a new SLN tracer method since 2005. Recent meta-analysis showed that ICG has SLN detection rate from 81.9% to 100% and sensitivity from 65.2% to 100%. No statistical difference in detection rate and sensitivity was found between ICG combined with RI tracer and ICG alone [17]. The key factor in evaluating the quality of SLNB is the false-negative rate. False negative means that metastatic lymph nodes are not detected, and the tumor stage is underestimated. This phenomenon leads to inadequate systemic treatment and increases the risk of local recurrence and distant metastasis. Another meta-analysis based on six studies reported 8% false negative rate when using ICG as a tracer [18]. In the National Surgical Adjuvant Breast and Bowel Project B-32 trial including 5611 patients with clinically negative axillary lymph nodes, a false negative rate of 9.8% is found when using combined blue dye and RI double tracer [4]; this value was comparable to that of ICG. Findings about the comparability of false negative rate (FNR) between ICG and dual tracer of RI and blue dye are inadequate and thus require additional clinical trials for validation. On the basis of the above data, MB combined with ICG can be a new dual-tracer method to replace RI plus blue dye, especially for institutions without access to RI. This novel method have the following advantages over the gold standard: a) projection real-time navigation with advanced image processing for lymphatic visualization, b) no involvement of physicians from the nuclear medicine department prior to the operation, and c) easy transportation and preservation.
The mean number of removed SLNs is 1.5–3.4 under the guidance of conventional NIR system with ICG fluorescence [11] and 3 under guidance of individual LFIS and conventional NIR system. The median number of SLNs excised by blue dye is 2, which is significantly lower than that by ICG methods (P<0.05). Compared with blue dye, the NIR fluorescence imaging system shows sensitivity even at low concentrations that are visible to the naked eye [19] and detects more SLNs. The increase in the number of SLNs detected within the appropriate range can avoid excessive interference in the axillary tissue and enable an accurate and full evaluation of lymph node condition. Extracting only one SLN has a high risk of false negative. To date, 3–4 SLNs are needed to identify more than 97% positive lymph nodes. In combination with postoperative complications, the extraction of no less than 4 SLNs is currently recommended [20].
In a case in this study, two SLNs were detected by the two fluorescence imaging systems but not by MB. These two lymph nodes were re moved and pathologically indicated as lacking lymph node tissues. This finding revealed the limitations of ICG as a tracer. The leakage of ICG caused by intraoperative lymphatic vessel damage and its high sensitivity resulted in the occurrence of non-lymph node fluorescence images in the operative field. This phenomenon is called “contamination”, which may cause the difficulty of lymph node localization.
In this study, three patients had no percutaneous fluorescence signal and superficial lymphangiography but showed ICG lymph nodes as revealed by conventional incision.Body Mass Index (BMI) is negatively correlated with lymphatic vessels, and injection depth and fat thickness are the main factors affecting ICG sensitivity [21]. However, no correlation was found between lymphatic vessels and the detection rate of fluorescent lymph nodes. In the three cases without lymphatic vessel images, fluorescent lymph nodes were observed through conventional incision. The surgeon’s intuitive feeling is that the difficulty of SLNB is relatively high for obese patients. Hence, the difficulty of surgery must be quantified afterward, and the operation time should be measured.
In this study, the number of ICG lymph nodes was negatively and weakly correlated with BMI. In a similar study, patients with high BMI (≥22 Kg/m²) have fewer removed SLNs than those with lower BMI, but no statistical difference was observed [22].